Propionic acid derivatives

ABSTRACT

This invention relates to novel potent PPAR-alpha-activating compounds which are useful in the treatment of diseases such as coronary heart disease. The invention also relates to methods of preparation of PPAR-alpha-activating compounds.

This application is a continuing application of U.S. Ser. No.09/973,753, filed Oct. 9, 2001, now U.S. Pat. No. 6,548,538.

The present invention relates to novel potent PPAR-alpha-activatingcompounds for treating, for example, coronary heart disease, and totheir preparation.

In spite of many successful therapies, coronary heart disease (CHD)remains a serious public health problem. Treatment with statins, whichinhibit HMG-CoA reductase, successfully lowers both LDL cholesterolplasma concentrations and the mortality of patients at risk; however,convincing treatment strategies for the therapy of patients having anunfavourable HDL/LDL cholesterol ratio or hypertriglyceridaemia arestill not available to date.

Currently, fibrates are the only therapy option for patients of theserisk groups. They act as weak agonists of theperoxisome-proliferator-activated receptor (PPAR)-alpha (Nature 1990,347, 645-50). A disadvantage of the fibrates which have hitherto beenapproved is that their interaction with the receptor is only weak,requiring high daily doses and causing considerable side-effects.

WO 00/23407 describes PPAR modulators for treating obesity,atherosclerosis and/or diabetes.

It was an object of the present invention to provide novel compoundswhich can be used as PPAR-alpha modulators.

It has now been found that this object is achieved by compounds of thegeneral formula (I)

in which

A represents a bond or represents a —CH₂— or —CH₂CH₂— group,

X represents O, S or CH₂,

R¹, R² and R³ are identical or different and independently of oneanother each represents hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl,hydroxyl, (C₁-C₆)-alkoxy, (C₆-C₁₀)-aryloxy, halogen, trifluoromethyl,trifluoromethoxy, (C₁-C₆)-alkylaminosulphonyl, nitro or cyano,

or

R¹ and R² are attached to two adjacent carbon atoms and together withthese form a fused cyclohexane or benzene ring, the latter optionallybeing substituted by a (C₁-C₄)-alkylsulphonylmethyl group,

and

R³ is as defined above,

R⁴ represents hydrogen or (C₁-C₄)-alkyl,

R⁵ and R⁶ represent hydrogen or together with the carbon atom to whichthey are attached form a carbonyl group,

R⁷ represents hydrogen, (C₁-C₆)-alkyl, phenyl or benzyl, where thearomatic radicals mentioned for their part may in each case be mono- totrisubstituted by identical or different substituents from the groupconsisting of (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, hydroxyl and halogen,

R⁸ represents hydrogen, (C₆-C₁₀)-aryl or represents (C₁-C₄)-alkyl whichfor its part may be substituted by hydroxyl, trifluoromethoxy,(C₁-C₄)-alkoxy or phenoxy, which for their part are optionally mono- ordisubstituted by trifluoromethyl, or by (C₆-C₁₀)-aryl or 5- or6-membered heteroaryl having up to three heteroatoms from the groupconsisting of N, O and S, where all aryl and hetaroaryl rings mentionedmay for their part in each case be mono- to trisubstituted by identicalor different substituents from the group consisting of halogen,hydroxyl, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, trifluoromethyl,trifluoromethoxy, cyano, nitro and amino,

R⁹ and R¹⁰ are identical or different and independently of one anothereach represents hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,trifluoromethyl, trifluoromethoxy or halogen,

R¹¹ and R¹² are identical or different and independently of one anothereach represents hydrogen or (C₁-C₆)-alkyl or together with the carbonatom to which they are attached form a (C₄-C₇)-cycloalkyl ring,

and

R¹³ represents hydrogen or represents a group which can hydrolysed anddegraded to the corresponding carboxylic acid,

and their pharmaceutically acceptable salts, hydrates and solvates,

which have pharmacological action and can be used as medicaments or forpreparing medicament formulations.

In the context of the invention, a hydrolysable group in the definitionof R¹³ is a group which, in particular in the body, leads to aconversion of the —C(O)OR¹³ grouping into the corresponding carboxylicacid (R¹³=hydrogen). Such groups are, by way of example and by way ofpreference: benzyl, (C₁-C₆)-alkyl or (C₃-C₈)-cycloalkyl which are ineach case optionally mono- or polysubstituted by identical or differentsubstituents from the group consisting of halogen, hydroxyl, amino,(C₁-C₆)-alkoxy, carboxyl, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)-alkoxycarbonylamino and (C₁-C₆)-alkanoyloxy, and in particular(C₁-C₄)-alkyl which is optionally mono- or polysubstituted by identicalor different substituents from the group consisting of halogen,hydroxyl, amino, (C₁-C₄)-alkoxy, carboxyl, (C₁-C₄)-alkoxycarbonyl,(C₁-C₄)-alkoxycarbonylamino and (C₁-C₄)-alkanoyloxy.

In the context of the invention, (C₁-C₆)-alkyl and (C₁-C₄)-alkylrepresent a straight-chain or branched alkyl radical having 1 to 6 or 1to 4 carbon atoms, respectively. Preference is given to a straight-chainor branched alkyl radical having 1 to 4 carbon atoms. The followingradicals may be mentioned by way of example and by way of preference:methyl, ethyl, n-propyl, isopropyl and tert-butyl.

In the context of the invention, (C₆-C₁₀)-aryl represents an aromaticradical having 6 to 10 carbon atoms. A preferred example is the arylradical phenyl.

In the context of the invention, (C₃-C₈)-cycloalkyl and(C₄-C₇)-cycloalkyl represent a cycloalkyl group having 3 to 8 and 4 to 7carbon atoms, respectively. The following radicals may be mentioned byway of example and by way of preference: cyclobutyl, cyclopentyl andcyclohexyl.

In the context of the invention, (C₁-C₆)-alkoxy represents astraight-chain or branched alkoxy radical having 1 to 6 carbon atoms.Preference is given to a straight-chain or branched alkoxy radicalhaving 1 to 4 carbon atoms. The following radicals may be mentioned byway of example and by way of preference: methoxy, ethoxy, n-propoxy,isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

In the context of the invention, (C₆-C₁₀)-aryloxy represents an aromaticradical having 6 to 10 carbon atoms which is attached via an oxygenatom. A preferred example is the aryloxy radical phenoxy.

In the context of the invention, (C₁-C₆)-alkoxycarbonyl represents astraight-chain or branched alkoxy radical having 1 to 6 carbon atomswhich is attached via a carbonyl group. Preference is given to astraight-chain or branched alkoxycarbonyl radical having 1 to 4 carbonatoms. The following radicals may be mentioned by way of example and byway of preference: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl and tert-butoxycarbonyl.

In the context of the invention, (C₁-C₆)-alkoxycarbonylamino representsan amino group having a straight-chain or branched alkoxycarbonylsubstituent which has 1 to 6 carbon atoms in the alkoxy radical and isattached via the carbonyl group. Preference is given to analkoxycarbonylamino radical having 1 to 4 carbon atoms. The followingradicals may be mentioned by way of example and by way of preference:methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino,isopropoxycarbonylamino and tert-butoxycarbonylamino.

In the context of the invention, (C₁-C₆)-alkanoyloxy represents astraight-chain or branched alkyl radical having 1 to 6 carbon atomswhich carries a doubly attached oxygen atom in the 1-position and isattached in the 1-position via a further oxygen atom. The followingradicals may be mentioned by way of example and by way of preference:acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy, n-hexanoyloxy.

In the context of the invention, (C₁-C₆)-alkylamninosulphonyl representsan amino group which is attached via a sulphonyl group and has astraight-chain or branched alkyl substituent having 1 to 6 carbon atoms.Preference is given to an alkylaminosulphonyl radical having 1 to 4carbon atoms. The following radicals may be mentioned by way of exampleand by way of preference: methylaminosulphonyl, ethylaminosulphonyl,n-propylaminosulphonyl, isopropylaminosulphonyl andtert-butylaminosulphonyl.

In the context of the invention, halogen represents fluorine, chlorine,bromine and iodine. Preference is given to chlorine or fluorine.

In the context of the invention, 5- or 6-membered heteroaryl having upto 3 heteroatoms selected from the group consisting of S, N and Ogenerally represents a monocyclic heteroaromatic radical which isattached via a ring carbon atom of the heteroaromatic radical, or, ifappropriate, via a ring nitrogen atom of the heteroaromatic radical. Thefollowing radicals may be mentioned by way of example and by way ofpreference: furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl,triazolyl, pyridyl, pyrimidyl, pyridazinyl. Preference is given tofuranyl, thienyl and oxazolyl.

Depending on the substitution pattern, the compounds according to theinvention can exist in stereoisomeric forms which are either like imageand mirror image (enantiomers) or which are not like image and mirrorimage (diastereomers). The invention relates both to the enantiomers ordiastereomers and to their respective mixtures. The racemic forms, likethe diastereomers, can be separated in a known manner into thestereoisomerically uniform components.

Furthermore, certain compounds may be present in tautomeric forms. Thisis known to the person skilled in the art, and such compounds arelikewise included within the scope of the invention.

The compounds according to the invention can also be present as salts.In the context of the invention, preference is given to physiologicallyacceptable salts.

Physiologically acceptable salts can be salts of the compounds accordingto the invention with inorganic or organic acids. Preference is given tosalts with organic acids such as, for example, hydrochloric acid,hydrobromic acid, phosphoric acid or sulphuric acid or to salts withorganic carboxylic or sulphonic acids such as, for example, acetic acid,propionic acid, maleic acid, fumaric acid, malic acid, citric acid,tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid,ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid ornaphthalene-disulphonic acid.

Physiologically acceptable salts can also be salts of the compoundsaccording to the invention with bases, such as, for example, metal orammonium salts. Preferred examples are alkali metal salts (for examplesodium salts or potassium salts), alkaline earth metal salts (forexample magnesium salts or calcium salts), and also ammonium salts whichare derived from ammonia or organic amines, such as, for example,ethylamine, di- or triethylamine, ethyldilsopropylamine,monoethanolamine, di- or triethanolamine, dicyclohexylamine,dimethylaminoethanol, dibenzylamine, N-methylmorpholine,dihydroabietylamine, 1-ephenamine, methylpiperidine, arginine, lysine,ethylenediamine or 2-phenylethylamine.

The compounds according to the invention can also be present in the formof their solvates, in particular in the form of their hydrates.

Preference is given to compounds of the general formula (I),

in which

A represents a bond or represents a —CH₂— or —CH₂CH₂— group,

X represents O, S or CH₂,

R¹, R² and R³ are identical or different and independently of oneanother each represents hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, nitro or cyano,

R⁴ represents hydrogen or (C₁-C₄)-alkyl,

R⁵ and R⁶ each represents hydrogen or together with the carbon atom towhich they are attached form a carbonyl group,

R⁷ represents hydrogen, (C₁-C₆)-alkyl, phenyl or benzyl, in which thearomatic radicals mentioned for their part may in each case be mono- totrisubstituted by identical or different substituents from the groupconsisting of (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, hydroxyl or halogen,

R⁸ represents hydrogen, (C₆-C₁₀)-aryl or (C₁-C₄)-alkyl, which for itspart is optionally substituted by (C₆-C₁₀)-aryl or 5- or 6-memberedheteroaryl having up to three heteroatoms from the group consisting ofN, O and S, where all of the ring systems mentioned may for their partin each case be mono- to trisubstituted by identical or differentsubstituents from the group consisting of halogen, hydroxyl,(C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, trifluoromethyl, trifluoromethoxy, cyano,nitro and amino,

R⁹ and R¹⁰ are identical or different and independently of one anothereach represents hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,trifluoromethyl, trifluoromethoxy or halogen,

R¹¹ and R¹² are identical or different and independently of one anothereach represents hydrogen or (C₁-C₆)-alkyl, or together with the carbonatom to which they are attached they form a (C₄-C₇)-cycloalkyl ring,

and

R¹³ represents hydrogen or a group that can be hydrolysed and degradedto the corresponding carboxylic acid,

and their pharmaceutically acceptable salts, hydrates and solvates.

Particular preference is given to compounds of the general formula (I),

in which

A represents a —CH₂— or —CH₂CH₂— group,

X represents O, S or CH₂,

R¹, R² and R³ are identical or different and independently of oneanother each represents hydrogen, (C₁-C₄)-alkyl, (C₁-C₄)-alkoxy,chlorine, fluorine, trifluoromethyl, trifluoromethoxy, nitro or cyano,

R⁴ represents hydrogen or methyl,

R⁵ and R⁶ each represent hydrogen or together with the carbon atom towhich they are attached form a carbonyl group,

R⁷ represents hydrogen, (C₁-C₄)-alkyl or benzyl,

R⁸ represents hydrogen, phenyl, benzyl or 5-membered heteroarylmethylhaving up to two heteroatoms from the group consisting of N, O and S,where the aromatic ring systems mentioned for their part may in eachcase be mono- to trisubstituted by identical or different substituentsfrom the group consisting of chlorine, fluorine, bromine, hydroxyl,(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy, trifluoromethyl and amino,

R⁹ and R¹⁰ are identical or different and independently of one anothereach represents hydrogen, (C₁-C₃)-alkyl, (C₁-C₃)-alkoxy,trifluoromethyl, fluorine or chlorine,

R¹¹ and R¹² are identical or diffferent and independently of one anothereach represents hydrogen, methyl or ethyl, or together with the carbonatom to which they are attached they form a cyclopentyl or cyclohexylring,

and

R¹³ represents hydrogen or represents a group that can be hydrolysed anddegraded to the corresponding carboxylic acid,

and their pharmaceutically acceptable salts, hydrates and solvates.

Very particular preference is given to compounds of the general formula(I),

in which

A represents a —CH₂— or —CH₂CH₂— group,

X represents O, S or CH₂,

R¹ represents hydrogen, methyl or methoxy,

R² and R³ are identical or different and independently of one anothereach represents methyl, trifluoromethyl, methoxy, trifluoromethoxy,chlorine or fluorine,

R⁴ represents hydrogen,

R⁵ and R⁶ together with the carbon atom to which they are attached forma carbonyl group,

R⁷ represents methyl, ethyl, n-propyl or, in particular, hydrogen,

R⁸ represents phenyl, furanylmethyl or thienylmethyl, where the ringsystems mentioned for their part may in each case be mono- ordisubstituted by identical or different substituents from the groupconsisting of methyl and ethyl,

R⁹ and R¹⁰ are identical or different and each represents hydrogen ormethyl in particular hydrogen,

R¹¹ and R¹² are identical or different and each represents hydrogen ormethyl in particular methyl,

and

R¹³ represents a group which can be hydrolysed and degraded to thecorresponding carboxylic acid, or, in particular, represents hydrogen,

and their pharmaceutically acceptable salts, hydrates and solvates.

The general or preferred radical definitions listed above apply both tothe end products of the formula (I) and, correspondingly, to thestarting materials and intermediates required in each case for thepreparation.

The individual radical definitions given in the respective combinationsor preferred combinations of radicals are, independently of therespective given combination of radicals, also replaced by any radicaldefinitions of other combinations.

Of particular importance are compounds of the formula (I) in which R⁴ ishydrogen.

Of particular importance are compounds of the formula (I) in which R⁵and R⁶ together with the carbon atom to which they are attached form acarbonyl group.

Of particular importance are compounds of the formula (I) in which

R¹ represents hydrogen, methyl or methoxy,

and

R² and R³ are identical or different and independently of one anothereach represents methyl, isopropyl, tert-butyl, cyclohexyl,trifluoromethyl, methoxy, trifluoromethoxy, chlorine or fluorine.

Of particular importance are compounds of the formula (I) in which

R⁸ represents phenyl, furanylmethyl, thienylmethyl or oxazolylmethyl,where the ring systems mentioned for their part may in each case bemono- or disubstituted by methyl, or represents 2-methoxyethyl.

Of very particular importance are compounds of the formula (IA)

in which

A represents a —CH₂— or —CH₂CH₂— group,

X represents O or S,

R¹ represents hydrogen, methyl or methoxy,

R² and R³ are identical or different and independently of one anothereach represents methyl, isopropyl, tert-butyl, cyclohexyl,trifluoromethyl, methoxy, trifluoromethoxy, chlorine or fluorine,

and

R⁸ represents phenyl, furanylmethyl, thienylmethyl or oxazolylmethyl,where the ring systems mentioned for their part may in each case bemono- or disubstituted by methyl, or represents 2-methoxyethyl.

Moreover, we have found a process for preparing the compounds of thegeneral formula (I) according to the invention, characterized in that

[A] compounds of the general formula (II)

in which

A, X, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each as defined above

and

T represents benzyl, (C₁-C₆)-alkyl or a polymeric support suitable forsolid-phase synthesis,

are initially, with activation of the carboxylic acid group in (II),reacted with compounds of the general formula (III)

in which

R¹, R² and R³ are each as defined above,

to give compounds of the general formula (Ia)

in which

A, X, T, R¹, R², R³, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each as definedabove,

or

[B] compounds of the general formula (IV)

in which

A, X, T, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each as defined above, are, in thepresence of a base, reacted with compounds of the general formula (V)

in which

R¹, R², R³ and R⁷ are each as defined above

and

Q is a suitable leaving group, for example halogen, mesylate ortosylate, preferably bromine or iodine,

likewise to compounds of the general formula (Ia)

the compounds of the general formula (Ia) are, if appropriate accordingto known methods for amide alkylation or amide reduction, converted intocompounds of the general formula (Ib)

in which

A, X, T, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are eachas defined above

then converted with acids or bases into the corresponding carboxylicacids of the general formula (Ic)

in which

A, X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each asdefined above,

and these are, if appropriate according to known methods foresterification, modified further by reaction with compounds of thegeneral formula (VI)

R¹³—Z  (VI),

in which

R¹³ is as defined above

and

Z represents a suitable leaving group for example halogen, mesylate ortosylate or represents a hydroxyl group.

The process according to the invention is generally carried out atatmospheric pressure. However, it is also possible to carry out theprocess under elevated pressure or under reduced pressure (for examplein a range of from 0.5 to 5 bar).

Solvents which are suitable for the process are customary organicsolvents which do not change under the reaction conditions. Theseinclude ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycoldimethyl ether, or hydrocarbons, such as benzene, toluene, xylene,hexane, cyclohexane or mineral oil fractions, or halogenatedhydrocarbons, such as dichloromethane, trichloromethane, carbontetrachloride, dichloroethylene, trichloroethylene or chlorobenzene, orethyl acetate, pyridine, dimethyl sulphoxide, dimethylformamide,N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP),acetonitrile, acetone or nitromethane. It is also possible to usemixtures of the solvents mentioned.

Solvents which are preferred for process step (II)+(III)→(Ia) aredichloromethane and dimethylformamide. For process step (IV)+(V)→(Ia),preference is given to dimethylformamide.

The process step (II)+(III)→(Ia) according to the invention is generallycarried out in a temperature range of from 0° C. to +100° C., preferablyfrom 0° C. to +40° C. The process step (IV)+(V)→(Ia) is generallycarried out in a temperature range of from 0° C. to +120° C., preferablyfrom +50° C. to +100° C.

The auxiliaries used for the amide formation in process step(II)+(III)→(Ia) are preferably customary condensing agents, such ascarbodiimides, for example, N,N′-diethyl-, N,N′-dipropyl-,N,N′-diisopropyl-, N,N′-dicyclohexylcarbodiimide (DCC),N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),or carbonyl compounds, such as carbonyldiimidazole, or 1,2-oxazoliumcompounds, such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulphate or2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds,such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic anhydride, or isobutyl chloroformate, orbis-(2-oxo-3-oxazolidinyl)-phosphoryl chloride orbenzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate, orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), if appropriate in combination with furtherauxiliaries such as 1-hydroxybenzotriazole or N-hydroxysuccinimide, andthe bases used are preferably alkali metal carbonates, for examplesodium carbonate or bicarbonate or potassium carbonate or bicarbonate,or organic bases, such as trialkylamines, for example triethylamine,N-methylmorpholine, N-methylpiperidine or diisopropylethylamine.Particular preference is given to the combination of EDC,N-methylmorpholine and 1-hydroxybenzotriazole, of EDC, triethylamine and1-hydroxybenzotriazole and of HATU and diisopropylethylamine.

Suitable bases for the reaction (IV)+(V)→(Ia) are the customaryinorganic bases, such as alkali metal alkoxides, such as, for example,lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metalcarbonates or alkaline earth metal carbonates, such as sodium carbonate,potassium carbonate, calcium carbonate or cesium carbonate, or sodiumbicarbonate or potassium bicarbonate, or organic bases, such astrialkylamines, for example triethylamine, N-methylmorpholine,N-methylpiperidine or diisopropylethylamine. Preference is given tosodium bicarbonate.

The hydrolysis of the carboxylic acid esters in the process step (Ia) or(Ib)→(Ic) is carried out by customary methods by treating the esters ininert solvents with bases, the salts that are initially formed beingconverted by treatment with acid into the free carboxylic acids. In thecase of the tert-butyl esters, the hydrolysis is preferably carried outusing acids.

Suitable solvents for the hydrolysis of the carboxylic acid esters arewater or the organic solvents which are customary for ester cleavage.These preferably include alcohols, such as methanol, ethanol, propanol,isopropanol or butanol, or ethers, such as tetrahydrofuran or dioxane,dimethylformamide, dichloromethane or dimethyl sulphoxide. It is alsopossible to use mixtures of the solvents mentioned. Preference is givento water/tetrahydrofuran and, in the case of the reaction withtrifluoroacetic acid, to dichloromethane and, in the case of hydrogenchloride, to tetrahydrofuran, diethyl ether, dioxane or water.

Bases suitable for the hydrolysis are the customary inorganic bases.These preferably include alkali metal hydroxide or alkaline earth metalhydroxide, such as, for example, sodium hydroxide, lithium hydroxide,potassium hydroxide or barium hydroxide, or alkali metal carbonates,such as sodium carbonate or potassium carbonate, or sodium bicarbonate.Particular preference is given to using sodium hydroxide or lithiumhydroxide.

Suitable acids are, in general, trifluoroacetic acid, sulphuric acid,hydrogen chloride, hydrogen bromide and acetic acid, or mixturesthereof, if appropriate with addition of water. Preference is given tohydrogen chloride or trifluoroacetic acid in the case of the tert-butylesters and to hydrochloric acid in the case of the methyl esters.

In the case of compounds of the general formula (Ia) or (Ib) prepared bysolid-phase synthesis and attached to a polymeric support via thecarboxylic acid group, the cleavage from the resin to give the compoundsof the general formula (Ic) is likewise carried out by theabove-described customary methods for carboxylic acid ester hydrolysis.Here, preference is given to using trifluoroacetic acid.

When carrying out the hydrolysis, the base or the acid is generallyemployed in an amount of from 1 to 100 mol, preferably from 1.5 to 40mol, based on 1 mole of the ester.

The hydrolysis is generally carried out in a temperature range of from0° C. to +100° C., preferably from 0° C. to +50° C.

The compounds of the general formula (II) are novel, and they can beprepared by initially

[a] reacting compounds of the general formula (VII)

in which

X, T, R⁹, R¹⁰, R¹¹ and R¹² are each as defined above

and

B represents a bond or a methylene group

in the presence of a suitable reducing agent with compounds of thegeneral formula (VIII)

 R¹⁴—NH₂  (VIII),

in which

R¹⁴ [a-1] has the meaning of R⁸ given above

or

[a-2] represents a group of the formula

in which

R⁷ is as defined above

and

R¹⁵ represents (C₁-C₄)-alkyl or trimethylsilyl,

to give compounds of the general formula (IX)

in which

B, X, T, R⁹, R¹⁰, R¹¹, R¹² and R¹⁴ are each as defined above,

then reacting these compounds in the presence of a base with compoundsof the general formula (X)

 R¹⁶—Y  (X),

in which

R¹⁶ in the case of process variant [a-1] represents a group of theformula

in which R⁷ and R¹⁵ are each as defined above

or,

in the case of process variant [a-2] has the meaning of R⁸ given aboveand

Y represents a suitable leaving group, such as, for example halogen,mesylate or tosylate, preferably bromine or iodine,

to give compounds of the general formula (XI)

in which

B, X, T, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹⁵ are each as defined above,

and finally selectively hydrolysing the carboxylic acid ester grouping—COOR¹⁵ in these compounds to the carboxylic acid,

or

[b] reacting compounds of the general formula (XII)

in which

A, X, T, R⁹, R¹⁰, R¹¹ and R¹² are each as defined above

in the presence of a suitable reducing agent with compounds of thegeneral formula (XIII)

R¹⁷—CHO  (XIII),

in which

R¹⁷ represents hydrogen, (C₆-C₁₀)-aryl, 5- or 6-membered heteroarylhaving up to three heteroatoms selected from the group consisting of N,O and S, or represents (C₁-C₃)-alkyl which for its part may besubstituted by hydroxyl, trifluoromethoxy, (C₁-C₄)-alkoxy or phenoxy,which for their part are optionally mono- or disubstituted bytrifluoromethyl, or by (C₆-C₁₀)-aryl or 5- to 6-membered heteroarylhaving up to three heteroatoms from the group consisting of N, O and S,where all aryl and heteroaryl rings mentioned may for their part in eachcase be mono- to trisubstituted by identical or different substituentsfrom the group consisting of halogen, hydroxyl, (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro andamino,

to give compounds of the general formula (XIV)

in which

A, X, T, R⁹, R¹⁰, R¹¹, R¹² and R¹⁷ are each as defined above,

then reacting these compounds in the presence of a base with compoundsof the general formula (XV)

in which

R⁷, R¹⁵ and Y are each as defined above

to give compounds of the general formula (XVI)

in which

A, X, T, R⁷, R⁹, R¹⁰, R¹¹, R¹², R¹⁵ and R¹⁷ are each as defined above,

and finally selectively hydrolysing the carboxylic acid ester grouping—COOR¹⁵ in these compounds to the carboxylic acid.

The entire process can also be carried out as solid-phase synthesis. Inthis case, the compounds of the general formula (VII) or (XII) areattached as carboxylic acid esters to a suitable support resin, thefurther reactions are carried out on solid phase and the target compoundis finally cleaved off from the resin. Solid-phase synthesis and theattachment and the cleavage from the resin are customary standardtechniques. To mention but one example from the extensive literature,reference is made to the publication “Linkers for Solid Phase OrganicSynthesis”, Ian W. James, Tetrahedron 55, 4855-4946 (1999).

The reaction (VII)+(VIII)→(IX) or (XII)+(XIII)→(XIV) is carried out inthe solvents which are customary for reductive amination and inert underthe reaction conditions, if appropriate in the presence of an acid. Thesolvents include, for example, water, dimethylformamide,tetrahydrofuran, dichloromethane, dichloroethane, or alcohols such asmethanol, ethanol, propanol, isopropanol or butanol; it is also possibleto use mixtures of the solvents mentioned. Preference is given tomethanol and ethanol in each case with addition of acetic acid.

Suitable reducing agents for the reaction (VII)+(VIII)→(IX) or(XII)+(XIII)→(XIV) are complex aluminium hydrides or boron hydrides,such as, for example, diisobutylaluminium hydride, sodium borohydride,sodium triacetoxyborohydride, sodium cyanoborohydride ortetrabutylammonium borohydride, or else catalytic hydrogenation in thepresence of transition metal catalysts such as, for example, palladium,platinum, rhodium or Raney nickel. Preferred reducing agents are sodiumcyanoborohydride, sodium triacetoxyborohydride and tetrabutylammoniumborohydride.

The reaction (VII)+(VIII)→(IX) or (XII)+(XIII)→(XIV) is generallycarried out in a temperature range of from 0° C. to +40° C.

The reaction (IX)+(X)→(XI) or (XIV)+(XV)→(XVI) is carried out in thecustomary solvents which are inert under the reaction conditions.Preference is given to dimethylformamide, tetrahydrofuran and dioxane.

Suitable bases for the reaction (IX)+(X)→(XI) or (XIV)+(XV)→(XVI) arethe customary inorganic or organic bases. Preference is given totriethylamine.

The reaction (IX)+(X)→(XI) or (XIV)+(XV)→(XVI) is generally carried outin a temperature range of from 0° C. to +100° C.

The reaction (XI)→(II) or (XVI)→(II) is carried out in the solventswhich are customary for ester cleavage and inert under the reactionconditions. In the case of the ester hydrolysis, these are preferablytetrahydrofuran, dioxane and alcohols, such as methanol and ethanol, ineach case in a mixture with water. In the case of the cleavage of silylesters, preference is given to using dioxane or tetrahydrofuran.

Suitable bases for the reaction (XI)→(II) or (XVI)→(II) are, in the caseof the hydrolysis, the customary inorganic bases. Preference is given tolithium hydroxide, sodium hydroxide and potassium hydroxide. In the caseof the cleavage of silyl esters, preference is given to usingtetrabutylammonium fluoride.

The reaction (XI)→(II) or (XVI)→(II) is generally carried out in atemperature range of from 0° C. to +100° C.

The compounds of the general formula (IV) correspond to the compounds ofthe general formula (IX) or (XIV) and can be prepared as describedabove.

The compounds of the general formulae (III), (V), (VI), (VII), (VIII),(X), (XII), (XIII) and (XV) are commercially available, known or can beprepared by customary methods [cf., for example, P. J. Brown et al., J.Med. Chem. 42, 3785-88 (1999)].

The compounds of the formula (I) according to the invention have asurprising and useful spectrum of pharmacological activity and cantherefore be used as versatile medicaments. In particular, they aresuitable for treating coronary heart diseases, for the prophylaxis ofmyocardial infarction and for the treatment of restenosis after coronaryangioplasty or stenting. The compounds of the formula (I) according tothe invention are preferably suitable for treating arteriosclerosis andhypercholesterolaemia, for increasing pathogenically low HDL levels andfor lowering elevated triglyceride, fibrinogen and LDL levels. Inaddition, they can be used for treating obesity, diabetes, for treatingthe metabolic syndrome (glucose intolerance, hyperinsulinaemia,dyslipidaemia and high blood pressure owing to insulin resistance),hepatic fibrosis and cancer.

The activity of the compounds according to the invention can beexamined, for example, in vitro by the transactivation assay describedin the experimental section.

The activity of the compounds according to the invention in vivo can beexamined, for example, by the tests described in the experimentalsection.

Suitable administration forms for administering the compounds of thegeneral formula (I) are all customary administration forms, i.e. oral,parenteral, inhalative, nasal, sublingual, rectal or external, forexample transdermal, preferably oral or parenteral, administrationforms. In the case of parenteral administration, particular mention hasto be made of intravenous, intramuscular and subcutaneousadministration, for example as a subcutaneous depot. Very particularpreference is given to oral administration.

Here, the active compounds can be administered on their own or in theform of preparations. Preparations suitable for oral administration are,inter alia, tablets, capsules, pellets, sugar-coated tablets, pills,granules, solid and liquid aerosols, syrups, emulsions, suspensions andsolutions. Here, the active compound has to be present in such an amountthat a therapeutic effect is obtained. In general, the active compoundcan be present in a concentration of from 0.1 to 100% by weight, inparticular from 0.5 to 90% by weight, preferably from 5 to 80% byweight. In particular, the concentration of active compound should be0.5-90% by weight, i.e. the active compound should be present in amountssufficient to reach the dosage range stated.

To this end, the active compounds can be converted in a manner known perse into the customary preparations. This is carried out using inertnon-toxic pharmaceutically suitable excipients, auxiliaries, solvents,vehicles, emulsifiers and/or dispersants.

Auxiliaries which may be mentioned are, for example: water, non-toxicorganic solvents, such as, for example, paraffins, vegetable oils (forexample sesame oil), alcohols (for example ethanol, glycerol), glycols(for example polyethylene glycol), solid carriers, such as natural orsynthetic ground minerals (for example talc or silicates), sugar (forexample lactose), emulsifiers, dispersants (for examplepolyvinylpyrrolidone) and glidants (for example magnesium sulphate).

In the case of oral administration, the tablets may, of course, alsocontain additives such as sodium citrate, together with additives suchas starch, gelatine and the like. Aqueous preparations for oraladministration may furthermore comprise flavour improvers or colorants.

In the case of oral administration, preference is given to administeringdosages of from 0.001 to 5 mg/kg, preferably from 0.005 to 3 mg/kg, ofbody weight per 24 hours.

The embodiments below illustrate the invention. The invention is notlimited to the examples.

The following abbreviations used represent:

Ac Acetyl Bu Butyl TLC Thin-layer chromatography DCI Direct chemicalionization (in MS) DCM Dichloromethane DIC Diisopropylcarbodiimide DMAP4-N,N-Dimethylaminopyridine DMF N,N-Dimethylformamidc DMSO Dimethylsuiphoxide EDC N′-(3-Dimethylaminopropyl)-N-ethylcarbodiimide × HCl EIElectron impact ionization (in MS) ESI Electron spray ionization (in MS)Et Ethyl sat. Saturated HATUO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate HOBt 1-Hydroxy-1H-benzotriazole × H₂O HPLCHigh-pressure, high-performance liquid chromatography LC-MS Liquidchromatography-coupled mass spectroscopy Me Methyl MS Mass spectroscopyNMR Nuclear magnetic resonance spectroscopy RF Reflux R_(f) Retentionindex (in TLC) RT Room temperature R_(t) Retention time (in HPLC) TBAFTetrabutylammonium fluoride TBAI Tetrabutylammonium iodide TFATrifluoroacetic acid THF Tetrahydrofuran

Starting Materials I EXAMPLE I-1 tert-Butyl 2-methylpropionate

With ice-cooling, a solution of 73.0 g (0.985 mol) of tert-butanol, 190g (1.877 mol) of triethylamine and 0.573 g (0.0047 mol) of DMAP in 750ml of dichloromethane is treated with a solution of 100 g (0.939 mmol)of isobutyryl chloride in 150 ml of dichloromethane, and the mixture isthen stirred overnight. 500 ml of 2 M hydrochloric acid are then added,the aqueous phase is extracted with dichloromethane and the combinedorganic phases are washed with water, sat. NaHCO₃ solution and sat. NaClsolution, dried over sodium sulphate and concentrated. Distillativepurification of the crude product gives 65.5 g (48%) of tert-butyl2-methylpropionate.

¹H-NMR (200 MHz, CDCl₃): δ=1.11 (d, 6H); 1.44 (s, 9H); 2.42 (sept., 1H).

EXAMPLE I-2 tert-Butyl 3-(4-bromophenyl)-2,2-dimethylpropionate

At −78° C., 34.7 ml (69.4 mmol) of a 2 M lithium diisopropylamidesolution are slowly added dropwise to a solution of 10.0 g (69.34 mmol)of tert-butyl 2-methylpropionate (Example I-1) in 100 ml oftetrahydrofuran. After the addition has ended, the mixture is stirred at−78° C. for 1 h, and a solution of 15.76 g (63.04 mmol) of 4-bromobenzylbromide in 10 ml of tetrahydrofuran is then added and the mixture isstirred at −78° C. for 1 h. The reaction is then warmed to roomtemperature and poured into 100 ml of 1 N hydrochloric acid, the phasesare separated and the aqueous phase is extracted 3× with diethyl ether.The combined organic phases are washed with NaHCO₃ solution, dried oversodium sulphate and freed from the solvent under reduced pressure.Distillative purification of the residue under oil pump vacuum gives16.75 g (85%) of tert-butyl 3-(4-bromophenyl)-2,2-dimethylpropionate.

¹H-NMR (200 MHz, DMSO): δ=1.06 (s, 6H); 1.38 (s, 9H); 2.74 (s, 2H); 7.10(d, 2H); 7.47 (d, 2H).

EXAMPLE I-3 tert-Butyl 3-(4-formylphenyl)-2,2-dimethylpropionate

At −75° C., 13.5 ml (22.98 mmol) of a 1.7 M tert-butyllithium solutionin pentane are slowly added to a solution of 6.00 g (19.16 mmol) oftert-butyl 3-(4-bromophenyl)-2,2-dimethylpropionate (Example I-2) in 80ml of tetrahydrofuran, the temperature being kept below −60° C. Themixture is stirred for 15 min, and 1.82 g (24.90 mmol) ofN,N-dimethylformamide are then added and the mixture is stirred at −75°C. for a further 4 h. The mixture is slowly warmed to −20° C. and, withvigorous stirring, admixed with 20 ml of water, and then warmed to roomtemperature. The aqueous phase is extracted 3× with diethyl ether andthe combined organic phases are dried over sodium sulfphate/sodiumcarbonate and freed from the solvent under reduced pressure.Distillation of the residue under oilpump vacuum gives 2.54 g (51%) oftert-butyl 3-(4-formylphenyl)-2,2-dimethylpropionate.

¹H-NMR (300 MHz, CDCl₃): δ=1.16 (s, 6H); 1.42 (s, 9H); 2.90 (s, 2H);7.32 (d, 2H); 7.78 (d, 2H); 9.98 (s, 1H).

EXAMPLE I-4 tert-Butyl 2-(4-formylphenoxy)-2-methylpropionate

A solution of 24.4 g (200 mmol) of 4-hydroxybenzaldehyde in 100 ml ofdimethylformamide is treated with 97.75 g (300 mmol) of caesiumcarbonate and stirred at 90° C. for 1 h. A solution of 66.93 g (300mmol) of tert-butyl 2-bromisobutyrate in 100 ml of dimethylformamide isthen added dropwise, and the mixture is stirred at 90° C. overnight. Thedimethylformamide is distilled off under reduced pressure and theresidue is then taken up in ethyl acetate, washed 2× with water, 2× with1 N aqueous sodium hydroxide solution and 1× with sat. NaCl solution,dried over sodium sulphate and freed from the solvent under reducedpressure. This gives 16.6 g (31%) of tert-butyl2-(4-formylphenoxy)-2-methylpropionate.

¹H-NMR (200 MHz, CDCl₃): δ=1.40 (s, 9H); 1.63 (s, 6H); 6.90 (d, 2H);7.78 (d, 2H); 9.88 (s, 1H).

EXAMPLE I-5 tert-Butyl3-(4-{[(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate

At room temperature, a solution of 1.00 g (3.81 mmol) of tert-butyl3-(4-formylphenyl)-2,2-dimethylpropionate (Example I-3) and 0.37 g (3.81mmol) of furfurylamine in 10 ml of dichloroethane is stirred for 30 min,1.21 g (5.72 mmol) of sodium triacetoxyborohydride are added and themixture is then stirred at room temperature for 22 h. 6 ml of sat.NaHCO₃ solution and 10 ml of ethyl acetate are then added, the phasesare separated, the aqueous phase is extracted 2× with ethyl acetate andthe combined organic phases are dried over sodium sulphate. The solventis removed under reduced pressure, and chromatographic purification onsilica gel (cyclohexane→cyclohexane/ethyl acetate 10:1→2:1) then gives720 mg (55%) of tert-butyl3-(4-{[(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate.

¹H-NMR (300 MHz, CDCl₃): δ=1.11 (s, 6H); 1.42 (s, 9H); 1.62 (broad s,1H); 2.70 (s, 2H); 3.76 (s, 2H); 3.80 (s, 2H); 6.18 (d, 1H); 6.32 (dd,1H); 7.10 (d, 2H); 7.20 (d, 2H); 7.35 (d, 1H).

EXAMPLE I-6 tert-Butyl3-[4-(anilinomethyl)phenyl]-2,2-dimethylpropionate

Similarly to the procedure of Example I-5, 200 mg (0.762 mmol) oftert-butyl 3-(4-formylphenyl)-2,2-dimethylpropionate (Example I-3), 71mg (0.762 mmol) of aniline and 210 mg (0.991 mmol) of sodiumtriacetoxyborohydride in 2 ml of dichloroethane are converted into 223mg (86%) of tert-butyl3-[4-(anilinomethyl)phenyl]-2,2-dimethylpropionate.

¹H-NMR (400 MHz, CDCl₃): δ=1.11 (s, 6H); 1.42 (s, 9H); 2.81 (s, 2H);3.98 (broad s, 1H); 4.29 (s, 2H); 6.64 (d, 2H); 6.71 (t, 1H); 7.12 (d,2H); 7.17 (t, 2H); 7.25 (d, 2H).

EXAMPLE I-7 tert-Butyl2,2-dimethyl-3-(4-{[(4-methylphenyl)amino]methyl}phenyl)propionate

Similarly to the procedure of Example I-5, 200 mg (0.762 mmol) oftert-butyl 3-(4-formylphenyl)-2,2-dimethylpropionate (Example I-3), 82mg (0.762 mmol) of toluidine and 210 mg (0.991 mmol) of sodiumtriacetoxyborohydride in 2 ml of dichloroethane are converted into 206mg (76%) of tert-butyl2,2-dimethyl-3-(4-{[(4-methylphenyl)amino]methyl}-phenyl)propionate.

¹H-NMR (400 MHz, CDCl₃): δ=1.11 (s, 6H); 1.42 (s, 9H); 2.23 (s, 3H);2.81 (s, 2H); 3.87 (broad s, 1H); 4.27 (s, 2H); 6.57 (d, 2H); 6.98 (d,2H); 7.12 (d, 2H); 7.25 (d, 2H).

EXAMPLE I-8 Methyl2-{[4-(2-tert-butoxy-1,1-dimethyl-2-oxoethoxy)benzyl]amino}butyrate

Similarly to the procedure of Example I-5, 1.20 g (4.54 mmol) oftert-butyl 2-(4-formylphenoxy)-2-methylpropionate (Example I-4) and 0.70g (4.54 mmol) of methyl DL-2-aminobutyrate are reacted at roomtemperature with 0.92 g (9.08 mmol) of triethylamine and 1.44 g (6.81mmol) of sodium triacetoxyborohydride in 10 ml of dichloroethane. Afurther 0.9 g (4.25 mmol) of sodium triacetoxyborohydride and 0.35 g(2.27 mmol) of methyl DL-2-aminobutyrate are added and the mixture isheated at 40° C. for 3 h, giving 1.47 g (89%) of methyl2-{[4-(2-tert-butoxy-1,1-dimethyl-2-oxoethoxy)benzyl]amino}butyrate.

¹H-NMR (300 MHz, DMSO): δ=0.84 (t, 3H); 1.38 (s, 9H); 1.47 (s, 6H); 1.57(dt, 2H); 2.29 (broad s, 1H); 3.08 (t, 1H); 3.47 (d, 1H); 3.62 (s, 3H);3.65 (d, 1H); 6.73 (d, 2H); 7.18 (d, 2H).

EXAMPLE I-9 tert-Butyl3-(4-{[(2-ethoxy-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate

A solution of 600 mg (1.75 mmol) of tert-butyl3-(4-{[(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate(Example I-5), 323 mg (0.87 mmol) of tetra-n-butylammonium iodide and265 mg (2.62 mmol) of triethylamine in 10 ml of THF is treated with 438mg (2.62 mmol) of ethyl bromoacetate and heated at reflux overnight.After cooling, the mixture is concentrated under reduced pressure, theresidue is taken up in water and ethyl acetate, the aqueous phase isextracted 2× with ethyl acetate and the combined organic phases arewashed with NaCl solution and dried over sodium sulphate. The solvent isremoved under reduced pressure, and chromatographic purification onsilica gel (cyclohexane→cyclohexane/ethyl acetate 10:1) then gives 702mg (94%) of tert-butyl3-(4-{[(2-ethoxy-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate.

¹H-NMR (400 MHz, CDCl₃): δ=1.11 (s, 6H); 1.27 (t, 3H); 1.42 (s, 9H);2.80 (s, 2H); 3.31 (s, 2H); 3.76 (s, 2H); 3.84 (s, 2H); 4.17 (q, 2H);6.20 (d, 1H); 6.32 (dd, 1H); 7.10 (d, 2H); 7.25 (d, 2H); 7.38 (d, 1H).

EXAMPLE I-10 tert-Butyl3-(4-{[N-(2-ethoxy-2-oxo)ethyl-N-phenylamino]methyl}phenyl)-2,2-dimethylpropionate

Similarly to the procedure of Example I-9, 198 mg (0.583 mmol) oftert-butyl 3-[4-(anilinomethyl)phenyl]-2,2-dimethylpropionate (ExampleI-6), 108 mg (0.292 mmol) of tetra-n-butylammonium iodide, two portionsof in each case 89 mg (0.875 mmol) of triethylamine and three portionsof in each case 146 mg (0.875 mmol) of ethyl bromoacetate in 2 ml oftetrahydrofuran and 2 ml of dimethylformamide give 191 mg (77%) oftert-butyl3-(4-{[(2-ethoxy-2-oxoethyl)(2-phenyl)amino]methyl}phenyl)-2,2-dimethylpropionate.

¹H-NMR (200 MHz, CDCl₃): δ=1.11 (s, 6H); 1.25 (t, 3H); 1.42 (s, 9H);2.70 (s, 2H); 4.05 (s, 2H); 4.20 (q, 2H); 4.62 (s, 2H); 6.69 (d, 2H);6.73 (t, 1H); 7.07-7.25 (m, 6H).

EXAMPLE I-11 tert-Butyl3-(4-{[N-(2-ethoxy-2-oxo)ethyl-N-(4-methylphenyl)amino]methyl}phenyl)-2,2-dimethylpropionate

Similarly to the procedure of Example I-9, 181 mg (0.512 mmol) oftert-butyl2,2-dimethyl-3-(4-{[(4-methylphenyl)amino]methyl}phenyl)propionate(Example I-7), 95 mg (0.256 mmol) of tetra-n-butylammonium iodide, twoportions of in each case 78 mg (0.768 mmol) of triethylamine and threeportions of in each case 128 mg (0.768 mmol) of ethyl bromoacetate in 2ml of tetrahydrofuran and 2 ml of dimethylformamide give 176 mg (78%) oftert-butyl3-(4-{[N-(2-ethoxy-2-oxo)ethyl-N-(4-methylphenyl)-amino]methyl}phenyl)-2,2-dimethylpropionate.

¹H-NMR (200 MHz, CDCl₃): 1.11 (s, 6H); 1.25 (t, 3H); 1.42 (s, 9H); 2.22(s, 3H); 2.80 (s, 2H); 4.02 (s, 2H); 4.19 (q, 2H); 4.59 (s, 2H); 6.60(d, 2H); 7.00 (d, 2H); 7.10 (d, 2H); 7.17 (d, 2H).

EXAMPLE I-12 N-[4-(3-tert-Butoxy2,2-dimethyl-3-oxopropyl)benzyl]-N-(2-furylmethyl)glycine

A solution of 785 mg (1.83 mmol) of tert-butyl3-(4-{[(2-ethoxy-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate(Example I-9) in 15 ml of ethanol is admixed with 5.5 ml (5.5 mmol) of 1N aqueous sodium hydroxide solution and heated at 80° C. for 1 h. Aftercooling, the mixture is concentrated under reduced pressure and theresidue is taken up in a little water, acidified with 1 N hydrochloricacid and extracted 3× with ethyl acetate. The combined organic extractsare washed 2× with sat. NaCl solution, dried over sodium sulphate andfreed from the solvent under reduced pressure. This gives 728 mg (99%)ofN-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-(2-furylmethyl)glycine.

¹H-NMR (200 MHz, DMSO): δ=1.06 (s, 6H); 1.37 (s, 9H); 2.74 (s, 2H); 3.24(s, 2H); 3.76 (s, 2H); 3.84 (s, 2H); 6.32 (m, 1H); 6.41 (m, 1H); 7.11(d, 2H); 7.26 (d, 2H); 7.63 (d, 1H); 12.20 (broad s, 1H).

EXAMPLE I-13N-[4-(3-tert-Butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-phenylglycine

Similarly to the procedure of Example I-12, 175 mg (0.411 mmol) oftert-butyl3-(4-{[(2-ethoxy-2-oxoethyl)(2-phenyl)amino]methyl}phenyl)-2,2-dimethylpropionate(Example I-10) and 1.23 ml (1.23 mmol) of 1 N aqueous sodium hydroxidesolution in 3 ml of ethanol give 162 mg (99%) ofN-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-phenylglycine.

¹H-NMR (300 MHz, DMSO): δ=1.04 (s, 6H); 1.36 (s, 9H); 2.73 (s, 2H); 4.12(s, 2H); 4.56 (s, 2H); 6.56 (d, 2H); 6.61 (t, 1H); 7.07 (d, 2H); 7.11(d, 2H); 7.19 (d, 1H); 12.53 (broad s, 1H).

EXAMPLE I-14N-[4-(3-tert-Butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-(4-methylphenyl)glycine

Similarly to the procedure of Example I-12, 153 mg (0.348 mmol) oftert-butyl3-(4-{[N-(2-ethoxy-2-oxo)ethyl-N-(4-methylphenyl)amino]methyl}phenyl)-2,2-dimethylpropionate(Example I-11) and 1.23 ml (1.23 mmol) of 1 N aqueous sodium hydroxidesolution in 3 ml of ethanol give 141 mg (99%) ofN-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-(4-methylphenyl)glycine.

¹H-NMR (300 MHz, DMSO): δ=1.04 (s, 6H); 1.36 (s, 9H); 2.14 (s, 3H); 2.72(s, 2H); 4.08 (s, 2H); 4.52 (s, 2H); 6.48 (d, 2H); 6.90 (d, 2H); 7.08(d, 2H); 7.18 (d, 2H); 12.48 (broad s, 1H).

EXAMPLE I-152-{[4-(2-tert-Butoxy-1,1-dimethyl-2-oxoethoxy)benzyl]amino}butyric acid

Similarly to the procedure of Example I-12, 750 mg (2.05 mmol) of methyl2-{[4-(2-tert-butoxy-1,1-dimethyl-2-oxoethoxy)benzyl]amino}butyrate(Example I-8) and 6.20 ml (6.20 mmol) of 1 N aqueous sodium hydroxidesolution in 6 ml of ethanol give 640 mg (89%) of2-{[4-(2-tert-butoxy-1,1-dimethyl-2-oxoethoxy)benzyl]amino}butyric acid.

¹H-NMR (300 MHz, DMSO): δ=0.91 (t, 3H); 1.40 (s, 9H); 1.51 (s, 6H); 1.84(m, 2H); 3.25 (broad s, 1H); 3.57 (t, 1H); 3.99 (s, 2H); 6.81 (d, 2H);7.38 (d, 2H).

WORKING EXAMPLES 1 Example 1-1 tert-Butyl3-(4-{[(2-(2,4-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate

At 0° C., 88 mg (0.648 mmol) of 1-hydroxy-1H-benzotriazole, 124 mg(0.648 mmol) of 1-ethyl-3-(3-dimethylamino)propylcarbodiimidehydrochloride, 151 mg (1.494 mmol) of N-methylmorpholine and 3 mg (0.025mmol) of 4-dimethylaminopyridine are added to a solution of 200 mg(0.498 mmol) ofN-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-(2-furylmethyl)glycine(Example I-12) and 91 mg (0.747 mmol) of 2,4-dimethylaniline in 8 ml ofdimethylformamide, and the solution is stirred at this temperature for 1h. The mixture is then stirred at room temperature for 9 h and thenadmixed with 10 ml of water. The aqueous phase is extracted 2× withethyl acetate and the combined organic phases are washed with 1 Nhydrochloric acid, sat. NaHCO₃ solution and sat. NaCl solution, driedover sodium sulphate and freed from the solvent under reduced pressure.Chromatographic purification of the residue on silica gel(cyclohexane/ethyl acetate 10:1→3:1) gives 228 mg (91%) of tert-butyl3-(4-{[(2-(2,4-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate.

¹H-NMR (200 MHz, CDCl₃): δ=1.10 (s, 6H); 1.40 (s, 9H); 2.26 (s, 3H);2.28 (s, 3H); 2.80 (s, 2H); 3.29 (s, 2H); 3.71 (s, 2H); 3.74 (s, 2H);6.25 (d, 1H); 6.32 (dd, 1H); 6.99 (m, 2H); 7.11 (d, 2H); 7.23 (d, 2H);7.37 (d, 1H); 7.84 (d, 1H); 9.12 (broad s, 1H).

Example 1-2 tert-Butyl3-(4-{[(2-(4-methoxy-2,5-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate

Similarly to the procedure of Example 1-1, 200 mg (0.498 mmol) ofN-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-(2-furylmethyl)glycine(Example I-12), 113 mg (0.747 mmol) of 4-methoxy-2,5-dimethylaniline, 88mg (0.648 mmol) of 1-hydroxy-1H-benzotriazole, 124 mg (0.648 mmol) of1-ethyl-3-(3-dimethylamino)-propylcarbodiimide hydrochloride, 151 mg(1.494 mmol) of N-methylmorpholine and 3 mg (0.025 mmol) of4-dimethylaminopyridine in 8 ml of dimethylformamide are converted into241 mg (90%) of tert-butyl3-(4-{[(2-(4-methoxy-2,5-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate.

¹H-NMR (200 MHz, DMSO): δ=1.05 (s, 6H); 1.35 (s, 9H); 2.08 (s, 3H); 2.14(s, 3H); 2.75 (s, 2H); 3.18 (s, 2H); 3.69 (s, 2H); 3.74 (s, 3H); 3.76(s, 2H); 6.35 (d, 1H); 6.41 (dd, 1H); 6.75 (s, 1H); 7.11 (d, 2H); 7.28(d, 2H); 7.31 (s, 1H); 7.61 (d, 1H); 9.02 (broad s, 1H).

Example 1-3 tert-Butyl3-(4-{[N-(2-(2,4-dimethylphenyl)amino-2-oxo)ethyl-N-phenylamino]methyl}phenyl)-2,2-dimethylpropionate

Similarly to the procedure of Example 1-1, 65 mg (0.164 mmol) ofN-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-phenylglycine(Example I-13), 30 mg (0.245 mmol) of 2,4-dimethylaniline, 29 mg (0.213mmol) of 1-hydroxy-1H-benzotriazole, 41 mg (0.213 mmol) of1-ethyl-3-(3-dimethylamino)propylcarbodiimide hydrochloride, 50 mg(0.491 mmol) of N-methylmorpholine and 0.2 mg (0.002 mmol) of4-dimethylaminopyridine in 2 ml of dimethylformamide are converted into65 mg (79%) of tert-butyl3-(4-{[N-(2-(2,4-dimethylphenyl)amino-2-oxo)ethyl-N-phenylamino]methyl}phenyl)-2,2-dimethylpropionate.

¹H-NMR (200 MHz, CDCl₃): δ=1.10 (s, 6H); 1.41 (s, 9H); 1.90 (s, 3H);2.26 (s, 3H); 2.79 (s, 2H); 4.09 (s, 2H); 4.66 (s, 2H); 6.80-6.95 (m,4H); 6.98 (d, 1H); 7.12 (s, 4H); 7.27 (m, 2H); 7.67 (d, 1H); 8.11 broads, 1H).

Example 1-4 tert-Butyl3-(4-{[N-(2-(4-methoxy-2,5-dimethylphenyl)amino-2-oxo)ethyl-N-phenylamino]methyl}phenyl)-2,2-dimethylpropionate

Similarly to the procedure of Example 1-1, 65 mg (0.164 mmol) ofN-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-phenylglycine(Example I-13), 37 mg (0.245 mmol) of 4-methoxy-2,5-dimethylaniline, 29mg (0.213 mmol) of 1-hydroxy-1H-benzotriazole, 41 mg (0.213 mmol) of1-ethyl-3-(3-dimethylamino)propylcarbodiimide hydrochloride, 50 mg(0.491 mmol) of N-methylmorpholine and 0.2 mg (0.002 mmol) of4-dimethylaminopyridine in 2 ml of dimethylformamide are converted into78 mg (90%) of tert-butyl3-(4-{[N-(2-(4-methoxy-2,5-dimethylphenyl)amino-2-oxo)ethyl-N-phenylamino]methyl}phenyl)-2,2-dimethylpropionate.

¹H-NMR (200 MHz, CDCl₃): δ=1.11 (s, 6H); 1.42 (s, 9H); 1.96 (s, 3H);2.16 (s, 3H); 2.80 (s, 2H); 3.77 (s, 3H); 4.09 (s, 2H); 4.67 (s, 2H);6.57 (s, 1H); 6.83 (dd, 1H); 6.89 (d, 2H); 7.13 (s, 4H); 7.24 (d, 2H);7.34 (m, 1H); 7.94 (broad s, 1H).

Example 1-5 tert-Butyl3-(4-{[N-(2-(2,4-dimethylphenyl)amino-2-oxo)ethyl-N-(4-methylphenyl)amino]methyl}phenyl)-2,2-dimethylpropionate

Similarly to the procedure of Example 1-1, 50 mg (0.121 mmol) ofN-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-(4-methylphenyl)glycine(Example I-14), 22 mg (0.182 mmol) of 2,4-dimethylaniline, 21 mg (0.158mmol) of 1-hydroxy-1H-benzotriazole, 30 mg (0.158 mmol) of1-ethyl-3-(3-dimethylamino)propylcarbodiimide hydrochloride, 37 mg(0.364 mmol) of N-methylmorpholine and 0.1 mg (0.001 mmol) of4-dimethylaminopyridine in 2 ml of dimethylformamide are converted into40 mg (64%) of tert-butyl-3-(4-{[N-(2-(2,4-dimethylphenyl)amino-2-oxo)ethyl-N-(4-methylphenyl)amino]methyl}phenyl)-2,2-dimethylpropionate.

¹H-NMR (300 MHz, CDCl₃): δ=1.10 (s, 6H); 1.40 (s, 9H); 1.92 (s, 3H);2.27 (s, 6H); 2.79 (s, 2H); 4.02 (s, 2H); 4.58 (s, 2H); 6.80 (d, 2H);6.91 (s, 1H); 6.98 (d, 1H); 7.06 (d, 2H); 7.11 (d, 2H); 7.13 (d, 2H);7.67 (d, 1H); 8.18 (broad s, 1H).

Example 1-6 tert-Butyl3-(4-{[N-(2-(4-methoxy-2,5-dimethylphenyl)amino-2-oxo)ethyl-N-(4-methylphenyl)amino]methyl}phenyl)-2,2-dimethylpropionate

Similarly to the procedure of Example 1-1, 50 mg (0.121 mmol) ofN-[4-(3-tert-butoxy-2,2-dimethyl-3-oxopropyl)benzyl]-N-(4-methylphenyl)glycine(Example I-14), 28 mg (0.182 mmol) of 4-methoxy-2,5-dimethylaniline, 21mg (0.158 mmol) of 1-hydroxy-1H-benzotriazole, 30 mg (0.158 mmol) of1-ethyl-3-(3-dimethylamino)propylcarbodiimide hydrochloride, 37 mg(0.364 mmol) of N-methylmorpholine and 0.1 mg (0.001 mmol) of4-dimethylaminopyridine in 2 ml of dimethylformamide are converted into58 mg (88%) ofter-butyl-3-(4-{[N-(2-(4-methoxy-2,5-dimethylphenyl)amino-2-oxo)ethyl-N-(4-methylphenyl)amino]methyl}phenyl)-2,2-dimethylpropionate.

¹H-NMR (300 MHz, CDCl₃): δ=1.10 (s, 6H); 1.41 (s, 9H); 1.96 (s, 3H);2.15 (s, 3H); 2.26 (s, 3H); 2.79 (s, 2H); 3.77 (s, 3H); 4.02 (s, 2H);4.60 (s, 2H); 6.57 (s, 1H); 6.80 (d, 2H); 7.07 (d, 2H); 7.10 (d, 2H);7.13 (d, 2H); 7.37 (s, 1H); 8.01 (broad s, 1H).

Example 1-7 tert-Butyl2-(4-{[(1-{[(2,4-dimethylphenyl)amino]carbonyl}propyl)-amino]methyl}-phenoxy)-2-methylpropionate

Similarly to the procedure of Example 1-1, 320 mg (0.90 mmol) of2-{[4-(2-tert-butoxy-1,1-dimethyl-2-oxoethoxy)benzyl]amino}butyric acid(Example I-15), 160 mg (1.36 mmol) of 2,4-dimethylaniline, 160 mg (1.18mmol) of 1-hydroxy-1H-benzotriazole, 230 mg (1.18 mmol) of1-ethyl-3-(3-dimethylamino)propylcarbodiimide hydrochloride, 270 mg(2.71 mmol) of N-methylmorpholine and 1 mg (0.01 mmol) of4-dimethylaminopyridine in 5 ml of dimethylformamide are converted into190 mg (46%) of tert-butyl2-(4-{[(1-{[(2,4-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}phenoxy)-2-methylpropionate.

¹H-NMR (200 MHz, CDCl₃): δ=0.99 (t, 3H); 1.43 (s, 9H); 1.56 (s, 6H);1.74 (m, 2H); 2.21 (s, 3H); 2.28 (s, 3H); 3.22 (dd, 1H); 3.69 (d, 1H);3.82 (d, 1H); 6.83 (d, 2H); 6.98 (s, 1H); 7.02 (d, 1H); 7.18 (d, 2H);7.93 (d, 1H); 9.32 (broad s, 1H).

Example 1-8 tert-Butyl2-(4-{[(1-{[(4-methoxy-2,5-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}phenoxy)-2-methylpropionate

Similarly to the procedure of Example 1-1, 320 mg (0.90 mmol) of2-{[4-(2-tert-butoxy-1,1-dimethyl-2-oxoethoxy)benzyl]amino}butyric acid(Example I-15), 210 mg (1.36 mmol) of 4-methoxy-2,5-dimethylaniline, 160mg (1.18 mmol) of 1-hydroxy-1H-benzotriazole, 230 mg (1.18 mmol) of1-ethyl-3-(3-dimethylamino)propylcarbodiimide hydrochloride, 270 mg(2.71 mmol) of N-methylmorpholine and 1 mg (0.01 mmol) of4-dimethylaminopyridine in 5 ml of dimethylformamide are converted into130 mg (30%) of tert-butyl2-(4-{[(1-{[(4-methoxy-2,5-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}phenoxy)-2-methylpropionate

¹H-NMR (200 MHz, CDCl₃): δ=0.99 (t, 3H); 1.44 (s, 9H); 1.56 (s, 6H);1.74 (m, 2H); 2.19 (s, 3H); 2.22 (s, 3H); 3.22 (dd, 1H); 3.71 (d, 1H);3.80 (s, 3H); 3.82 (d, 1H); 6.64 (s, 1H); 6.83 (d, 2H); 7.19 (d, 2H);7.65 (s, 1H); 9.13 (broad s, 1H).

Example 1-93-(4-{[(2-(2,4-Dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionicacid

A solution of 192 mg (0.380 mmol) of tert-butyl3-(4-{[(2-(2,4-dimethylphenyl)-amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate(Example 1-1) in 1 ml of dichloromethane is treated with 1 ml oftrifluoroacetic acid and stirred at room temperature for 2 h. Themixture is then concentrated under reduced pressure, the residue istaken up in ethyl acetate and the organic phase is washed 2× with water,1× with 20% strength sodium acetate solution, 1× with water and 1× withsat. NaCl solution, dried over sodium sulphate and freed from thesolvent under reduced pressure. Chromatographic purification of theresidue on silica gel (dichloromethane→dichloromethane/methanol 20:1)gives 150 mg (88%) of3-(4-{[(2-(2,4-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionicacid.

¹H-NMR (200 MHz, CDCl₃): δ=1.16 (s, 6H); 2.26 (s, 3H); 2.28 (s, 3H);2.87 (s, 2H); 3.30 (s, 2H); 3.71 (s, 2H); 3.74 (s, 2H); 6.26 (d, 1H);6.32 (dd, 1H); 6.99 (m, 2H); 7.12 (d, 2H); 7.24 (d, 2H); 7.37 (d, 1H);7.83 (d, 1H); 9.12 (broad s, 1H).

Example 1-103-(4-{[(2-(4-Methoxy-2,5-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionicacid

Similarly to the procedure of Example 1-9, 170 mg (0.318 mmol) oftert-butyl3-(4-{[(2-(4-methoxy-2,5-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate(Example 1-2) are reacted with 1 ml of trifluoroacetic acid in 1 ml ofdichloromethane to give 133 mg (87%) of3-(4-{[(2-(4-methoxy-2,5-dimethylphenyl)amino-2-oxoethyl)(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionicacid.

¹H-NMR (200 MHz, DMSO): δ=1.04 (s, 6H); 2.07 (s, 3H); 2.13 (s, 3H); 2.76(s, 2H); 3.18 (s, 2H); 3.70 (s, 2H); 3.74 (s, 3H); 3.76 (s, 2H); 6.39(d, 2H); 6.87 (s, 1H); 7.12 (d, 2H); 7.28 (d, 2H); 7.30 (s, 1H); 7.61(s, 1H); 9.02 (broad s, 1H); 12.18 (broad s, 1H).

Example 1-113-(4-{[N-(2-(2,4-Dimethylphenyl)amino-2-oxo)ethyl-N-phenylamino]methyl}phenyl)-2,2-dimethylpropionicacid

Similarly to the procedure of Example 1-9, 48 mg (0.096 mmol) oftert-butyl3-(4-{[N-(2-(2,4-dimethylphenyl)amino-2-oxo)ethyl-N-phenylamino]methyl}phenyl)-2,2-dimethylpropionate(Example 1-3) are reacted with 1 ml of trifluoroacetic acid in 2 ml ofdichlormethane to give 36 mg (85%) of3-(4-{[N-(2-(2,4-dimethylphenyl)amino-2-oxo)ethyl-N-phenylamino]methyl}phenyl)-2,2-dimethylpropionicacid.

¹H-NMR (200 MHz, CDCl₃): δ=1.19 (s, 6H); 1.90 (s, 3H); 2.26 (s, 3H);2.87 (s, 2H); 4.08 (s, 2H); 4.66 (s, 2H); 6.80-6.95 (m, 4H); 6.98 (d,1H); 7.14 (s, 4H); 7.27 (m, 2H); 7.67 (d, 1H); 8.08 (broad s, 1H).

Example 1-123-(4-{[N-(2-(4-Methoxy-2,5-dimethylphenyl)amino-2-oxo)ethyl-N-phenylamino]methyl}phenyl)-2,2-dimethylpropionicacid

Similarly to the procedure of Example 1-9, 61 mg (0.115 mmol) oftert-butyl3-(4-{[N-(2-(4-methoxy-2,5-dimethylphenyl)amino-2-oxo)ethyl-N-phenylamino]methyl}phenyl)-2,2-dimethylpropionate(Example 1-4) are reacted with 1 ml of trifluoroacetic acid in 2 ml ofdichloromethane to give 46 mg (85%) of3-(4-{[N-(2-(4-methoxy-2,5-dimethylphenyl)amino-2-oxo)ethyl-N-phenylamino]methyl}phenyl)-2,2-dimethylpropionicacid.

¹H-NMR (200 MHz, CDCl₃): δ=1.19 (s, 6H); 1.94 (s, 3H); 2.15 (s, 3H);2.86 (s, 2H); 3.77 (s, 3H); 4.08 (s, 2H); 4.66 (s, 2H); 6.56 (s, 1H);6.83 (dd, 1H); 6.88 (d, 2H); 7.13 (s, 4H); 7.24 (d, 2H); 7.34 (m, 1H);7.93 (broad s, 1H).

Example 1-133-(4-{[N-(2-(2,4-Dimethylphenyl)amino-2-oxo)ethyl-N-(4-methylphenyl)amino]methyl}phenyl)-2,2-dimethylpropionicacid

Similarly to the procedure of Example 1-9, 23 mg (0.049 mmol) oftert-butyl3-(4-{[N-(2-(2,4-dimethylphenyl)amino-2-oxo)ethyl-N-(4-methylphenyl)amino]methyl}phenyl)-2,2-dimethylpropionate(Example 1-5) are reacted with 1 ml of trifluoroacetic acid in 2 ml ofdichloromethane to give 20 mg (91%) of3-(4-{[N-(2-(2,4-dimethylphenyl)amino-2-oxo)ethyl-N-(4-methylphenyl)amino]methyl}phenyl)-2,2-dimethylpropionicacid.

¹H-NMR (200 MHz, CDCl₃): δ=1.17 (s, 6H); 1.92 (s, 3H); 2.25 (s, 6H);2.86 (s, 2H); 4.02 (s, 2H); 4.60 (s, 2H); 6.79 (d, 2H); 6.91 (s, 1H);6.98 (d, 1H); 7.06 (d, 2H); 7.13 (s, 2H); 7.17 (d, 2H); 7.68 (d, 1H);8.19 (broad s, 1H).

Example 1-143-(4-{[N-(2-(4-Methoxy-2,5-dimethylphenyl)amino-2-oxo)ethyl-N-(4-methylphenyl)amino]methyl}phenyl)-2,2-dimethylpropionicacid

Similarly to the procedure of Example 1-9, 40 mg (0.073 mmol) oftert-butyl3-(4-{[N-(2-(4-methoxy-2,5-dimethylphenyl)amino-2-oxo)ethyl-N-(4-methylphenyl)amino]methyl}phenyl)-2,2-dimethylpropionate(Example 1-6) are reacted with 1 ml of trifluoroacetic acid in 2 ml ofdichloromethane to give 33 mg (93%) of3-(4-{[N-(2-(4-methoxy-2,5-dimethylphenyl)amino-2-oxo)ethyl-N-(4-methylphenyl)amino]methyl}phenyl)-2,2-dimethylpropionicacid.

¹H-NMR (200 MHz, CDCl₃): δ=1.18 (s, 6H); 1.96 (s, 3H); 2.15 (s, 3H);2.26 (s, 3H); 2.86 (s, 2H); 3.76 (s, 3H); 4.03 (s, 2H); 4.61 (s, 2H);6.57 (s, 1H); 6.80 (dd, 2H); 7.07 (d, 2H); 7.14 (s, 4H); 7.36 (s, 1H);8.02 (broad s, 1H).

Example 1-152-(4-{[(1-{[(2,4-Dimethylphenyl)amino]carbonyl}propyl)amino]methyl}phenoxy)-2-methylpropionicacid

Similarly to the procedure of Example 1-9, 170 mg (0.374 mmol) oftert-butyl2-(4-{[(1-{[(2,4-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}phenoxy)-2-methylpropionate(Example 1-7) are reacted with 0.72 ml (9.35 mmol) of trifluoroaceticacid in 3 ml of dichloromethane to give 113 mg (72%) of2-(4-{[(1-{[(2,4-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}phenoxy)-2-methylpropionicacid.

¹H-NMR (300 MHz, CDCl₃): δ=1.01 (t, 3H); 1.53 (d, 6H); 1.95 (m, 2H);2.10 (s, 3H); 2.23 (s, 3H); 3.67 (broad s, 1H); 4.02 (m, 1H); 4.55 (m,1H); 6.61 (d, 2H); 6.82 (d, 1H); 6.89 (s, 1H); 7.10 (d, 2H); 7.11 (s,1H); 9.53 (broad s, 1H).

Example 1-162-(4-{[(1-{[(4-Methoxy-2,5-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}phenoxy)-2-methylpropionicacid

Similarly to the procedure of Example 1-9, 115 mg (0.237 mmol) oftert-butyl2-(4-{[(1-{[(4-methoxy-2,5-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}phenoxy)-2-methylpropionate(Example 1-8) are reacted with 0.46 ml (5.93 mmol) of trifluoroaceticacid in 3 ml of dichloromethane to give 100 mg (93%) of2-(4-{[(1-{[(4-methoxy-2,5-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}phenoxy)-2-methylpropionicacid.

¹H-NMR (300 MHz, CDCl₃): δ=1.05 (t, 3H); 1.55 (d, 6H); 1.97 (m, 2H);2.10 (s, 6H); 3.75 (s, 3H); 3.78 (m, 1H); 4.08 (m, 2H); 4.50 (m, 2H);6.50 (s, 1H); 6.64 (d, 2H); 6.94 (s, 1H); 7.14 (d, 2H); 7.65 (s, 1H);9.38 (broad s, 1H).

Starting Materials II EXAMPLE II-1 1,1-Dimethylethyl2-[(4-bromophenyl)thio]-2-methyl-propanoate

4-Bromothiophenol (100 g) and tert-butyl 2-bromoisobutyrate (118 g) aredissolved in 1 l of ethanol and treated with 29 g of KOH. The mixture isstirred under reflux for 2 h and cooled, and the KBr is filtered off.The filtrate is concentrated and the residue is recrystallized fromn-hexane. This gives 93.6 g of a colourless solid.

¹H-NMR (200 MHz, CDCl₃): 1.48 (s, 15H); 7.38 (m, 4H).

EXAMPLE II-2 1,1-Dimethylethyl2-[(4-formylphenyl)thio]-2-methyl-propanoate

1.0 g of 1,1-dimethylethyl 2-[(4-bromophenyl)thio]-2-methyl-propanoateis dissolved in 20 ml of THF and treated with 189 ml (3.02 mmol, 1 eq)of n-butyllithium solution in hexane. Directly afterwards, 0.46 ml ofdimethylformamide are added and the mixture is warmed to roomtemperature and stirred for 1 hour. The reaction is quenched by additionof 1 ml 1 N HCl, the mixture is concentrated and the residue is taken upin ethyl acetate. The mixture is extracted with sat. NaHCO₃ solution andwith NaCl solution and dried (MgSO₄). Chromatographic purification(dichloromethane) gives 550 mg of a pale yellow oil.

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=4.86 min([M+H]⁺=281).

EXAMPLE II-3 1,1-Dimethylethyl2-[[4-[[(2-furanylmethyl)amino]methyl]phenyl]thio]-2-methyl-propanoate

550 mg of 1,1-dimethylethyl 2-[(4-formylphenyl)thio]-2-methyl-propanoateand 381 mg of furfurylamine are initially charged in 100 ml of methanoland treated with 1 ml of glacial acetic acid. The mixture is stirred atroom temperature for 15 min, briefly brought to the boil and then, at 0°C., admixed a little at a time with 493 mg of sodium cyanoborohydride.The mixture is stirred overnight at room temperature and then treatedwith 1 N HCl and stirred for 30 min. The mixture is then made basicusing Na₂CO₃ solution and extracted 2× with ethyl acetate. The organicphase is washed (sat. NaCl solution) and dried (MgSO₄). Concentrationand chromatographic purification (dichloromethane/ethyl acetate 10+1)gives 430 mg of a colourless oil.

¹H-NMR (300 MHz, CDCl₃): 1.42 (s, 15H); 3.79 (s, 2H); 3.80 (s, 2H); 6.15(m, 1H); 6.28 (m, 1H); 7.25-7.45 (m, 5H).

EXAMPLE II-4 1,1-Dimethylethyl2-[[4-[2-[(2-ethoxy-2-oxoethyl)(2-furanylmethyl)amino]methyl]phenyl]thio]-2-methyl-propanoate

5.4 g of 1,1-dimethylethyl2-[[4-[[(2-furanylmethyl)amino]methyl]phenyl]thio]-2-methyl-propanoateare dissolved in 270 ml of tetrahydrofuran and treated with 2.27 g oftriethylamine and 3.74 g of ethyl bromoacetate and 14.85 g oftetra-n-butyl-ammonium iodide. The mixture is stirred at 90° C. for 48h, cooled and mixed with water and ethyl acetate. The organic phase isseparated off and washed twice with sat. NaCl solution. The mixture isdried (MgSO₄) and concentrated and the residue is purifiedchromatographically (cyclohexane/ethyl acetate 5+1), giving 6.4 g of acolourless oil.

¹H-NMR (CDCl₃, 200 MHz): 1.28 (t, 3H, J=8.7 Hz); 1.40 (s, 9H); 1.42 (s,6H); 3.32 (s, 2H); 3.78 (s, 2H); 3.84 (s, 2H); 4.15 (q, J=8.7 Hz); 6.17(m, 1H); 6.30 (m, 1H); 7.25-7.45 (m, 5H).

EXAMPLE II-52-[[4-[2-[(Carboxymethyl)(2-furanylmethyl)amino]methyl]phenyl]thio]-2-methyl-1,1-dimethylethylpropanoate

192 mg of 1,1-dimethylethyl2-[[4-[2-[(2-ethoxy-2-oxoethyl)(2-furanylmethyl)amino]methyl]phenyl]-thio]-2-methyl-propanoateare initially charged in 5 ml of ethanol and treated with 0.4 ml 1 NNaOH. The mixture is stirred at 80° C. for 1 h. The mixture is checkedby TLC (CH₂Cl₂/methanol=10+1) and then cooled and concentrated, and theresidue is dissolved in a little water. The mixture is acidified using 1N HCl and extracted three times with ethyl acetate. The combined organicphases are washed 2× with water and 2× with sat. NaCl solution and driedover MgSO₄. The mixture is concentrated, applied to silica gel andpurified by flash chromatography using CH₂Cl₂→CH₂Cl₂/methanol 50+1→25+1.This gives 132 mg of a colourless oil which solidifies under highvacuum.

¹H-NMR (DMSO, 200 MHz): 1.32 (s, 9H); 1.39 (s, 6H); 3.18 (s, 2H); 3.22(s, 2H); 3.23 (s, 2H); 6.27 (m, 1H); 6.40 (m, 1H); 7.34 (d, 2H, J=9.0Hz); 7.50 (d, 2H, J=9.0 Hz); 7.59 (m, 1H); 12.38 (broad s, 1H).

EXAMPLE II-6 1,1-Dimethylethyl2-[[4-[2-[(2-furanylmethyl)amino]ethyl]phenyl]thio]-2-methyl-propanoate

4.0 g of 1,1-dimethylethyl2-[[4-(2-aminoethyl)phenyl]thio]-2-methyl-propanoate [(P. J. Brown etal., J. Med. Chem. 42, 3785-88 (1999)] are dissolved in 100 ml ofmethanol and treated with 2.6 g of furfural. 9.3 ml of glacial aceticacid are added and the mixture is boiled briefly (10 min). The mixtureis then cooled to 0° C., and 4.25 g of sodium cyanoborohydride are addeda little at a time. The mixture is then stirred at room temperatureovernight. 1 N HCl is added until the mixture is acidic, and the mixtureis stirred for 30 min. The mixture is concentrated slightly and madebasic using sat. NaHCO₃ solution. The mixture is then extracted twicewith ethyl acetate and the extracts are washed (sat. NaCl solution) anddried and concentrated. Chromatographic purification(dichloromethane/methanol 15+1) gives 2.4 g of the title compound as acolourless oil.

R_(f) (Dichloromethane/methanol 10+1)=0.57.

EXAMPLE II-7 1,1-Dimethylethyl2-[[4-[2-[(2-ethoxy-2-oxoethyl)(2-furanylmethyl)amino]ethyl]phenyl]thio]-2-methyl-propanoate

2.4 g of 1,1-dimethylethyl2-[[4-[2-[(2-furanylmethyl)amino]ethyl]phenyl]thio]-2-methyl-propanoate,1.5 g of ethyl bromoacetate, 0.97 g of triethylamine and 7.08 g oftetra-n-butylammonium iodide are dissolved in 100 ml of tetrahydrofuranand heated at reflux overnight. Ethyl acetate and water are added, andthe mixture is extracted with water and sat. NaCl solution.Concentration and chromatography (petroleum ether/ethyl acetate 10+1)gives 1.38 g of the title compound.

¹H-NMR (DMSO, 200 MHz): 1.18 (t, 3H, J=7.8 Hz); 1.37 (s, 15H); 2.77 (m4H); 3.32 (s, 2H); 3.81 (s, 2H); 4.06 (q, 2H, J=7.8 Hz); 6.21 (m, 1H);6.34 (m, 1H); 7.16 (d, 2H, J=9.6 Hz); 7.32 (d, 2H, J=9.6 Hz); 7.58 (m,1H).

EXAMPLE II-8 1,1-Dimethylethyl2-[[4-[2-[(carboxymethyl)(2-furanylmethyl)amino]ethyl]phenyl]thio]-2-methyl-propanoate

1.0 g of 1,1-dimethylethyl2-[[4-[2-[(2-ethoxy-2-oxoethyl)(2-furanylmethyl)amino]ethyl]phenyl]thio]-2-methyl-propanoateis treated with 6.5 ml of 1 N NaOH in 10 ml of ethanol. The mixture isstirred at 80° C. for 1 h, concentrated, dissolved in water andacidified with 1 N HCl. Three extractions with ethyl acetate andchromatography (dichloromethane/methanol 5+1) gives 744 mg as acolourless oil.

¹H-NMR (DMSO, 200 MHz): 1.36 (s, 15H); 2.75 (m, 4H); 3.20 (s, 2H); 3.72(s, 2H); 6.18 (m, 1H); 6.88 (m, 1H); 7.12 (d, 2H, J=9.5 Hz); 7.32 (d,2H, J=9.5 Hz); 7.56 (m, 1H).

EXAMPLE II-9 1,1-Dimethylethyl2-[[4-[[(2-methoxyethyl)amino]methyl]phenyl]thio]-2-methyl-propanoate

7.9 g of 1,1-dimethylethyl 2-[(4-formylphenyl)thio]-2-methyl-propanoateand 4.23 g of methoxyethylamine are initially charged in 100 ml ofmethanol and admixed with 19 ml of acetic acid. The mixture is stirredat RT for 15 min, boiled briefly and then, at 0° C., admixed a little ata time with 8.9 g of sodium cyanoborohydride. The mixture is stirred atroom temperature overnight and then admixed with 1 N HCl and stirred for30 min. The mixture is then made basic using sodium carbonate solutionand extracted 2× with ethyl acetate. The organic phase is washed withsat. sodium chloride solution and dried over magnesium sulphate.Concentration and chromatographic purification give 5.6 g (58%) of acolourless oil.

¹H-NMR (200 MHz, CDCl₃): δ=1.38 (s, 6H), 1.42 (s, 9H), 2.45 (m, 3H,CH₂+NH), 3.37 (s, 3H), 3.88 (s, 2H), 7.25-7.52 (m, 4H).

EXAMPLE II-10 1,1-Dimethylethyl2-[[4-[[(2-(5-methylfuranmethyl)amino]methyl]phenyl]thio]-2-methyl-propanoate

8.0 g 1,1-dimethylethyl 2-[(4-formylphenyl)thio]-2-methyl-propanoate and6.3 g of 5-methyl-2-furanmethanamine are initially charged in 100 ml ofmethanol and treated with 16 ml of acetic acid. The mixture is stirredat RT for 15 min, boiled briefly and then, at 0° C., admixed a little ata time with 5.7 g of sodium cyanoborohydride. The mixture is stirred atroom temperature overnight and then admixed with 1 N HCl and stirred for30 min. The mixture is then made basic using sodium carbonate solutionand extracted 2× with ethyl acetate. The organic phase is washed withsat. sodium chloride solution and dried over magnesium sulphate.Concentration and chromatographic purification gives 4.8 g (45%) of acolourless oil which tends to decompose and is stored at −25° C.

¹H-NMR (200 MHz, CDCl₃): δ=1.42 (s, 15H), 1.72 (s, 1H, NH), 2.28 (s,3H), 3.79 (s, 2H), 3.78 (s, 2H), 5.88 (m, 1H), 6.03 (m, 1H), 7.28 (dd,2H, J=11 Hz), 7.45 (m, 2H, J=11 Hz).

EXAMPLE II-11 2-Bromo-N-(2,4-dimethylphenyl)-acetamide

117 g of triethylamine and 140 g of 2,4-dimethylaniline are dissolved in2 l of methylene chloride, and a solution of 233 g of alpha-bromoacetylbromide in 400 ml of methylene chloride is added with ice-cooling, at atmost 15° C., within 30 min. After a reaction time of 30 min, theprecipitate is filtered off with suction, the residue is dissolved in 3l of methylene chloride and combined with the filtrate and washed twicewith 2 l of water and 2 l of sat. sodium chloride solution. The mixtureis dried over sodium sulphate, filtered off with suction andconcentrated, and the residue is recrystallized from ethanol. This gives193 g of the title compound.

EXAMPLE II-12 2-Bromo-N-(2,4-dichlorophenyl)-acetamide

This compound was prepared similarly to Example II-11 from 4.2 g of2,4-dichloroaniline and 5.76 g of bromoacetyl bromide and 2.89 g oftriethylamine in methylene chloride. This gave 5.9 g (80.4%) of thetitle compound.

R_(f) (Dichloromethane): 0.38

MS (EI pos.): M⁺=283.

WORKING EXAMPLES 2 Example 2-1 tert-Butyl2-[[4-[[[2-[(2,4-dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)-amino]-methyl]phenyl]thio]-2-methyl-propanoate

Method a):

250 mg of2-[[4-[2-[(carboxymethyl)(2-furanylmethyl)amino]methyl]-phenyl]thio]-2-methyl-1,1-dimethylethylpropanoate, 89 mg of hydroxybenzotriazole, 249 ml of triethylamine, 82mg of 2,4-dimethylaniline and 131 mg ofN′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride aredissolved in 5 ml of dichloromethane. The mixture is stirred at roomtemperature for 20 h and extracted with 1 N NaOH, 1 N HCl, water andsat. NaCl solution. The combined organic phases are dried (MgSO₄) andpurified chromatographically (dichloromethane/ethyl acetate 25+1). Thisgives 200 mg of a viscous oil.

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=4.87 min([M+H]⁺=523).

Method b):

1.5 g of 1,1-dimethylethyl2-[[4-[[(2-furanylmethyl)amino]methyl]phenyl]thio]-2-methyl-propanoate(Example II-3) and 1.1 g of 2-bromo-N-(2,4-dimethylphenyl)-acetamide(Example II-9) are dissolved in 20 ml of DMF and treated with 0.4 g ofsodium bicarbonate. The mixture is heated at 90° C. overnight,concentrated and purified chromatographically (dichloromethane/ethylacetate 10:1 and 5:1). This gives 2.1 g of the title compound.

Example 2-2 tert-Butyl2-[[4-[[[2-[(2,4,6-trimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)-amino]-methyl]phenyl]thio]-2-methyl-propanoate

250 mg of2-[[4-[2-[(carboxymethyl)(2-furanylmethyl)amino]methyl]-phenyl]thio]-2-methyl-1,1-dimethylethylpropanate, 90 mg of hydroxybenzotriazole, 250 ml of triethylamine, 80 mgof 2,4,6-trimethylaniline and 130 mg ofN′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride aredissolved in 5 ml of dichloromethane. The mixture is stirred at roomtemperature for 20 h and extracted with 1 N NaOH, 1 N HCl, water andsat. NaCl solution. The combined organic phases are dried (MgSO₄) andpurified chromatographically (dichloromethane/ethyl acetate 25+1). Thisgives 210 mg of a viscous oil.

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=5.32 min([M+H]⁺=537).

Example 2-3 tert-Butyl2-[[4-[[[2-[(2,5-dimethyl-4-methoxyphenyl)amino]-2-oxoethyl](2-furanylmethyl)-amino]methyl]phenyl]thio]-2-methyl-propanoate

250 mg of2-[[4-[2-[(carboxymethyl)(2-furanylmethyl)amino]-ethyl]-phenyl]thio]-2-methyl-1,1-dimethylethylpropanoate, 90 mg of hydroxybenzotriazole, 250 ml of triethylamine, 80mg of 2,5-dimethyl-4-methoxyaniline and 130 mg ofN′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride aredissolved in 5 ml of dichloromethane. The mixture is stirred at roomtemperature for 20 h and extracted with 1 N NaOH, 1 N HCl, water andsat. NaCl solution. The combined organic phases are dried (MgSO₄) andpurified chromatographically (dichloromethane/ethyl acetate 25+1). Thisgives 190 mg of a viscous oil.

LC-MS: Acetonitrile/30% aqueous HCl/water (Gradient): R_(t)=4.90 min([M+H]⁺=552).

Example 2-4 tert-Butyl2-[[4-[[[2-[(2-methyl-4-methoxyphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]-methyl]phenyl]thio]-2-methyl-propanoate

250 mg of2-[[4-[2-[(carboxymethyl)(2-furanylmethyl)amino]-ethyl]-phenyl]thio]-2-methyl-1,1-dimethylethylpropanoate, 90 mg of hydroxybenzotriazole, 250 ml of triethylamine, 80mg of 2-methyl-4-methoxylaniline and 130 mg ofN′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride aredissolved in 5 ml of dichloromethane. The mixture is stirred at roomtemperature for 20 h and extracted with 1 N NaOH, 1 N HCl, water andsat. NaCl solution. The combined organic phases are dried (MgSO₄) andpurified chromatographically (dichloromethane/ethyl acetate 25+1). Thisgives 190 mg of a viscous oil.

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=4.69 min([M+H]⁺=538).

Example 2-52-[[4-[[[2-[(2,4-Dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]-methyl]phenyl]thio]-2-methyl-propanoicacid

90 mg of tert-butyl2-[[4-[[[2-[(2,4-dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]-methyl]phenyl]thio]-2-methyl-propanoateare dissolved in 5 ml of dichloromethane and reacted with 0.1 ml oftrifluoroacetic acid. The mixture is stirred at room temperature for 4 hand then concentrated and purified chromatographically(dichloromethane/methanol 100+1). This gives 80 mg of the title compoundas a solid foam.

R_(f) (Dichloromethane/methanol 10+1)=0.3

¹H-NMR (400 MHz, D₆-DMSO): δ=1.34 (s, 6H, CH₃), 2.16 (s, 3H, CH₃), 2.23(s, 3H, CH₃), 3.24 (s, 2H, CH₂), 3.76 (s, 2H, CH₂), 3.78 (s, 2H, CH₂),6.38-6.40 (m, 2H, 2× furanyl-H), 6.93-6.95 (d, 2H, Ar—H), 7.0 (s, 1H,Ar—H), 7.38-7.51 (m, 4H, Ar—H), 7.60-7.61 (m, 1H, furanyl-H), 9.14 (s,1H, NH).

MS (ESI pos.): m/z=467 ([M+H]⁺), m/z=489 ([M+Na]⁺)

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=3.76 min([M+H]⁺=467).

Example 2-5a2-[[4-[[[2-[(2,4-Dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]-methyl]phenyl]thio]-2-methyl-propanoicacid dicyclohexylammonium salt

500 mg of2-[[4-[[[2-[(2,4-dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenyl]thio]-2-methyl-propanoicacid (Example 2-5) are dissolved in 500 mg of acetonitrile, and 194 mgof dicyclohexylamine are added. Water is added, some of the acetonitrileis distilled off until the mixture becomes turbid and the mixture islyophilized. This gives 445 mg of a powder.

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=3.76 min([M+H]⁺=467).

Example 2-5b2-[[4-[[[2-[(2,4-Dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]-methyl]phenyl]thio]-2-methyl-propanoicacid hydrochloride

1.20 g of2-[[4-[[[2-[(2,4-dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]-methyl]phenyl]thio]-2-methyl-propanoicacid (Example 2-5) are dissolved in 100 ml of ethyl acetate and admixedwith 1N HCl/diethyl ether until the mixture becomes turbid. Theresulting crystals are filtered off with suction and washed with dryether. This gives 1 g of the title compound.

M.p.: 158° C. (from ethanol/diethyl ether).

Example 2-62-[[4-[[[2-[(2,4,6-Trimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]-methyl]phenyl]thio]-2-methyl-propanoicacid

210 mg of tert-butyl2-[[4-[[[2-[(2,4,6-trimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)-amino]methyl]phenyl]thio]-2-methyl-propanoateare dissolved in 5 ml of dichloromethane and reacted with 1 ml oftrifluoroacetic acid. The mixture is stirred at room temperature for 4 hand then concentrated and purified chromatographically(dichloromethane/ethyl acetate 50+1). This gives 187 mg of the titlecompound as a solid foam.

¹H-NMR (DMSO, 200 MHz): 1.42 (s, 6H); 2.04 (s, 6H); 2.23 (s, 3H); 3.58(broad s, 2H); 4.05 (s, 2H); 4.12 (s, 2H); 6.55 (m, 2H); 6.87 (s, 2H);7.48 (d, 2H, J=9.0 Hz); 7.51 (d, 2H, J=9.0 Hz); 7.72 (m, 1H); 9.40(broad s, 1H).

Example 2-72-[[4-[[[2-[(2,5-Dimethyl-4-methoxyphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenyl]thio]-2-methyl-propanoicacid

190 mg of tert-butyl2-[[4-[[[2-[(2,5-dimethyl-4-methoxyphenyl)amino]-2-oxoethyl](2-furanyl-methyl)amino]methyl]phenyl]thio]-2-methyl-propanoateare dissolved in 5 ml of dichloromethane and reacted with 1 ml oftrifluoroacetic acid. The mixture is stirred at room temperature for 20h and then concentrated and purified chromatographically(dichloromethane/methanol 50+1). This gives 166 mg of the title compoundas a solid foam.

¹H-NMR (DMSO, 200 MHz): 1.39 (s, 6H); 2.08 (s, 3H); 2.11 (s, 3H); 3.7(s, 3H); 4.00 (broad s, 4H); 6.48 (m, 1H); 6.51 (m, 1H); 6.76 (s, 1H);7.08 (s, 1H); 7.48 (m, 4H); 7.72 (m, 1H); 9.35, (broad s, 1H); 12.65(broad s, 1H).

Example 2-82-[[4-[[[2-[(2-Methyl-4-methoxyphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenyl]thio]-2-methyl-propanoicacid

200 mg of tert-butyl2-[[4-[[[2-[(2-methyl-4-methoxyphenyl)amino]-2-oxoethyl](2-furanyl-methyl)amino]methyl]phenyl]thio]-2-methyl-propanoateare dissolved in 5 ml of dichloromethane and reacted with 1 ml oftrifluoroacetic acid. The mixture is stirred at room temperature for 20h and then concentrated and purified chromatographically(dichloromethane/methanol 50+1). This gives 174 mg of the title compoundas a solid foam.

¹H-NMR (DMSO, 200 MHz): 1.38 (s, 6H); 2.12 (s, 3H); 3.7 (s, 3H); 3.80(broad s, 2H); 4.00 (broad s, 2H); 6.45 (m, 1H); 6.55 (m, 1H); 6.65 (m,1H); 6.78 (m, 1H); 7.25 (m, 1H); 7.48 (m, 4H); 7.71 (m, 1H); 9.37 (broads, 1H); 12.65 (broad s, 1H).

Example 2-9 tert-Butyl2-[[4-[2-[[2-[(2,4-dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]-ethyl]phenyl]thio]-2-methyl-propanoate

104 mg of 1,1-dimethylethyl2-[[4-[2-[(carboxymethyl)(2-furanylmethyl)amino]-ethyl]phenyl]thio]-2-methyl-propanoate,36 mg of hydroxybenzotriazole, 0.1 ml of triethylamine, 29 mg of2,4-dimethylaniline and 53 mg ofN′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride aredissolved in 5 ml of dichloromethane. The mixture is stirred at roomtemperature for 20 h and extracted with 1 N NaOH, 1 N HCl, water andsat. NaCl solution. The combined organic phases are dried (MgSO₄) andpurified chromatographically (dichloromethane/ethyl acetate 5+1). Thisgives 190 mg of a viscous oil.

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=5.3 min([M+H]⁺=537).

¹H-NMR (CDCl₃, 200 MHz): 1.38 (s, 9H); 1.40 (s, 6H); 2.08 (s, 3H); 2.28(s, 3H); 2.82 (m, 4H); 3.32 (s, 2H); 3.78 (s, 2H); 6.22 (m, 1H); 6.95(m, 1H); 7.00 (m, 1H); 7.05 (d, 2H, J=10.0 Hz); 7.35 (d, 2H, J=10.0 Hz),including: (m, 1H); 7.79 (m, 1H); 8.95 (broad s, 1H); 12.60 (broad s,1H).

Example 2-10 tert-Butyl2-[[4-[2-[[2-[(2,5-dimethyl-4-methoxyphenyl)amino]-2-oxoethyl](2-furanylmethyl)-amino]ethyl]phenyl]thio]-2-methyl-propanoate

98 mg of 1,1-dimethylethyl2-[[4-[2-[(carboxymethyl)(2-furanylmethyl)amino]-ethyl]phenyl]thio]-2-methyl-propanoate,33 mg of hydroxybenzotriazole, 0.09 ml of triethylamine, 34 mg of2,5-dimethyl-4-methoxyaniline and 49 mg ofN′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride aredissolved in 5 ml of dichloromethane. The mixture is stirred at roomtemperature for 20 h and extracted with 1 N NaOH, 1 N HCl, water andsat. NaCl solution. The combined organic phases are dried (MgSO₄) andpurified chromatographically (dichloromethane/ethyl acetate 5+1). Thisgives 48 mg of a viscous oil.

TLC: R_(f)=0.65 (dichloromethane/ethyl aceta=10+1).

Example 2-112-[[4-[2-[[2-[(2,4-Dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]-ethyl]phenyl]thio]-2-methyl-propanoicacid

38 mg of tert-butyl2-[[4-[2-[[2-[(2,4-dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)-amino]ethyl]phenyl]thio]-2-methyl-propanoateare dissolved in 5 ml of dichloromethane and treated with 0.27 ml oftrifluoroacetic acid. The mixture is stirred at room temperature for 24h and co-evaporated with toluene, and the residue is chromatographed(dichloromethane/methanol 10+1). This gives 33 mg of a colourless oil.

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=3.38 min([M+H]⁺=481).

Example 2-122-[[4-[2-[[2-[(2,5-Dimethyl-4-methoxyphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]ethyl]phenyl]thio]-2-methyl-propanoicacid

30 mg of tert-butyl2-[[4-[2-[[2-[(2,5-dimethyl-4-methoxyphenyl)amino]-2-oxoethyl](2-furanyl-methyl)amino]ethyl]phenyl]thio]-2-methyl-propanoateare dissolved in 5 ml of dichloromethane and treated with 0.20 ml oftrifluoroacetic acid. The mixture is stirred at room temperature for 24h and co-evaporated with toluene, and the residue is chromatographed(dichloromethane/methanol 10+1). This gives 27 mg of an oil which turnsdark when exposed to the atmosphere.

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=3.78 min([M+H]⁺=511).

¹H-NR (DMSO, 200 MHz): 1.35 (s, 9H); 2.05 (s, 3H); 2.10 (s, 3H); 2.82(m, 4H); 3.25 (s, 2H); 3.72 (s, 3H); 3.82 (s, 2H); 6.33 (m, 2H); 6.72(m, 1H); 7.15 (d, 2H, J=9.8 Hz); 7.24(d, 2H, J=9.8 Hz), including: (m,1H); 7.62 (m, 1H); 8.88 (broad s, 1H); 12.55 (broad s, 1H).

The following exemplary compounds were prepared in a similar manner:

Example 2-132-Methyl-2-[[4-[[[(5-methyl-2-furanyl)methyl][2-oxo-2-[(2,4-dichlorophenyl)amino]ethyl]amino]methyl]phenyl]thio]-propanoicacid

Yield: 343 mg (68%).

¹H-NMR: (200 MHz, CDCl₃): δ=1.50 (s, 6H, 2×CH₃), 2.19 (s, 3H, CH₃), 3.38(s, 2H, CH₂), 3.78 (s, 2H, CH₂), 3.83 (s, 2H, CH₂), 4.30 (s, br, 1H,COOH), 5.85 (m, 1H, furanyl-H), 6.16 (m, 1H, furanyl-H), 7.18-7.49 (m,6H, Ar—H), 8.30 (m, 1H, Ar—H), 9.68 (s, 1H, NH).

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=3.42 min([M+H]⁺=521)

Example 2-142-Methyl-2-[[4-[[[(5-methyl-2-furanyl)methyl][2-oxo-2-[(2,4,6-trichlorophenyl)amino]ethyl]amino]methyl]phenyl]thio]-propanoicacid

Yield: 90 mg (36%)

¹H-NMR (200 MHz, CDCl₃): δ=1.53 (s, 6H, 2×CH₃), 2.29 (s, 3H, CH₃), 3.75(s, 2H, CH₂), 4.25 (s, 2H, CH₂), 4.28 (s, 2H, CH₂), 5.95 (m, 1H,furanyl-H), 6.49 (m, 1H, furanyl-H), 7.35 (s, 2H, Ar—H), 7.38-7.51 (m,4H, A—H), 9.51 (s, 1H, NH).

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=3.05 min([M+H]⁺=555)

Example 2-152-Methyl-2-[[4-[[[(5-methyl-2-furanyl)methyl][2-oxo-2-[(2,4,6-trimethylphenyl)amino]ethyl]amino]methyl]phenyl]thio]-propanoicacid

Yield: 46 mg (26%)

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=4.18 min([M+H]⁺=494)

Example 2-162-Methyl-2-[[4-[[[(5-methyl-2-furanyl)methyl][2-oxo-2-[(2,4-dimethylphenyl)amino]ethyl]amino]methyl]phenyl]thio]-propanoicacid

Yield: 183 mg (41%)

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=2.80 min([M+H]⁺=481)

Example 2-17 2-Methyl-2-[[4-[[[(5-methyl -2-furanyl)methyl][2-oxo-2-[(2,5-dimethyl-4-methoxyphenyl)amino]ethyl]amino]methyl]phenyl]thio]-propanoicacid

Yield: 149 mg (67%)

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=4.10 min([M+H]⁺=511)

Example 2-182-Methyl-2-[[4-[[[(5-methyl-2-furanyl)methyl][2-oxo-2-[(4-chloro-2-trifluoromethylphenyl)amino]ethyl]amino]methyl]phenyl]thio]-propanoicacid

Yield: 63 mg (22%)

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=3.48 min([M+H]⁺=555)

Example 2-192-Methyl-2-[[4-[[[(5-methyl-2-furanyl)methyl][2-oxo-2-[(4-methoxy-2-methylphenyl)amino]ethyl]amino]methyl]phenyl]thio]-propanoicacid

Yield: 24 mg (18%)

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=2.59 min([M+H]⁺=497)

Example 2-202-[[4-[[[2-[(2,5-Dimethyl-4-methoxy-phenyl)amino]-2-oxoethyl](2-methoxyethyl)-amino]methyl]phenyl]thio]-2-methyl-propionicacid

Yield: 60 mg (60%)

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=2.15 min([M+H]⁺=475).

Example 2-212-Methyl-2-[[4-[[[(5-methyl-2-furanyl)methyl][2-oxo-2-[(2,4-bistrifluoromethylphenyl)amino]ethyl]amino]methyl]phenyl]thio]-propanoicacid

Yield: 16 mg (20%)

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=3.59 min([M+H]⁺=589)

Example 2-222-Methyl-2-[[4-[[[(5-methyl-2-furanyl)methyl][2-oxo-2-[(2-methyl-4-trifluoromethoxy-5-chlorophenyl)amino]ethyl]amino]methyl]phenyl]thio]-propanoicacid

Yield: 89 mg (81%)

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=3.36 min([M+H]⁺=585)

Example 2-232-Methyl-2-[[4-[[[(5-methyl-2-furanyl)methyl][2-oxo-2-[(2-trifluoromethyl-4-trifluoromethoxyphenyl)amino]ethyl]amino]methyl]phenyl]thio]-propanoicacid

Yield: 22 mg (34%)

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=3.52 min([M+H]⁺=605)

Example 2-242-[[4-[[[2-[[2,4-Bis(trifluoromethyl)phenyl]amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]phenyl]thio]-2-methyl-propanoicacid

Yield: 26 mg (20%)

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=3.05 min([M+H]⁺=553).

Example 2-252-[[4-[[[2-[[2,4-Dichlorophenyl]amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]phenyl]thio]-2-methyl-propanoicacid

Yield: 61 mg (27%).

¹H-NMR (300 MHz, CDCl₃): δ=1.38 (s, 6H, 2×CH₃), 2.82 (m, 2H, CH₂), 3.23(s, 3H, OMe), 3.32 (s, 2H, CH₂), 3.50 (m, 2H, CH₂), 3.73 (s, 2H, CH₂),5.28 (s, 1H, COOH), 7.15-7.48 (m, 6H, Ar—H), 8.35 (m, 1H, Ar—H), 9.90(s, 1H, NH).

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=2.76 min([M+H]⁺=485).

Example 2-262-[[4-[[[2-[[2,4-Dimethylphenyl]amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]phenyl]thio]-2-methyl-propanoicacid

Yield: 50 mg (75%)

¹H-NMR (200 MHz, CDCl₃): δ=1.50 (s, 6H, 2×CH₃), 2.15 (s, 3H, Me), 2.28(s, 3H, Me), 3.34 (s, 3H, OMe), 3.40 (m, 2H, CH₂), 3.68 (m, 2H, CH₂),3.83 (s, 2H, CH₂), 4.32 (s, 2H, CH₂), 5.40 (s, 1H, COOH), 7.00 (m, 2H,Ar—H), 7.32-7.52 (m, 7H, Ar—H), 9.00 (s, 1H, NH).

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=2.22 min([M+H]⁺=445).

Example 2-272-Methyl-2-[[4-[[[(2-thiophenyl)methyl][2-oxo-2-[(2-methyl-4-trifluoromethoxy-5-chlorophenyl)amino]ethyl]amino]methyl]phenyl]thio]-propanoicacid

Yield: 200 mg (99%)

¹H-NMR (300 MHz, CDCl₃): δ=1.50 (s, 6H, 2×CH₃), 2.20 (s, 3H, Me), 3.61(s, 2H, CH₂), 4.20 (s, 2H, CH₂), 4.48 (s, 2H, CH₂), 5.60 (s, 1H, COOH),7.00 (m, 2H, Ar—H), 7.02-7.17 (m, 3H, Ar—H and thienyl-H), 7.36 (m, 3H,Ar—H), 7.50 (m, 2H, Ar—H), 8.00 (s, 1H, Ar H), 8.88 (s, 1H, NH).

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=3.40 min([M+H/]⁺=587).

Example 2-282-Methyl-2-[[4-[[[(2-thiophenyl)methyl][2-oxo-2-[(2-trifluoromethyl-4-trifluoromethoxy-phenyl)amino]ethyl]amino]methyl]phenyl]thio]-propanoicacid

Yield: 80 mg (98%)

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=3.56 min([M+H]⁺=606).

Example 2-29 2-Methyl-2-[[4-[[[(2-thiophenyl)methyl][2-oxo-2-[(2-methyl-4-methoxy-phenyl)amino]ethyl]amino]methyl]phenyl]thio]-propanoicacid

Yield: 83 mg (83%)

LC-MS: Acetonitrile/30% aqueous UCI/water (gradient): R_(t)=2.74 min([M+H]⁺=498).

Example 2-302-Methyl-2-[[4-[[[(2-furanyl)methyl][2-oxo-2-[(2,4-dimethoxyphenyl)amino]ethyl]amino]methyl]phenyl]thio]-propanoicacid

Yield: 75 mg (60%)

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=4.19 min([M+H]⁺=499).

Example 2-312-[[4-[[[2-[(2-Methyl-4-methoxyphenyl)amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]phenyl]thio]-2-methyl-propanoicacid

Yield: 65% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.51 (s, 6H); 2.18 (s, 3H); 3.34 (s, 3H);3.37-3.45 (m, 2H); 3.65-3.75 (m, 2H); 3.77 (s, 3H); 3.89 (s, 2H); 4.34(s, 2H); 6.67-6.78 (m, 2H); 7.35-7.44 (m, 3H); 7.52 (d, 2H); 9.05 (s,1H).

Example 2-322-[[4-[[[2-[(2,4,6-Trimethylphenyl)amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]phenyl]thio]-2-methyl-propanoicacid

Yield: 89% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.51 (s, 6H); 2.12 (s, 6H); 2.25 (s, 3H);3.35 (s, 3H); 3.38-3.54 (m, 2H); 3.65-3.77 (m, 2H); 3.85-3.94 (m, 2H);4.30-4.45 (m, 2H); 6.87 (s, 2H); 7.39 (d, 2H); 7.53 (d, 2H); 8.82 (br s,1H).

Starting Materials III EXAMPLE III-1 tert-Butyl (4-formylphenoxy)acetate

At room temperature, 31.60 g (281.48 mmol) of potassium tert-butoxideand 52.70 g (270.22 mmol) of tert-butyl bromoacetate are added to asolution of 27.50 g (225.18 mmol) of 4-hydroxybenzaldehyde in 200 ml ofdioxane, and the mixture is heated at the boil overnight. 1 l of wateris added, and the mixture is then extracted with diethyl ether, washedwith 1 N sodium hydroxide solution, water and saturated sodium chloridesolution and dried over magnesium sulphate, and the solvent is distilledoff. Flash chromatography on silica gel (cyclohexane→cyclohexane/ethylacetate 20:1→10:1→5:1) gives, after recrystallization from pentane, thetarget compound.

Yield: 31%

Melting point: 58-60° C.

EXAMPLE III-2 tert-Butyl 2-(4-formylphenoxy)-2-methylpropanoate

24.42 g (200 mmol) of 4-hydroxybenzaldehyde are dissolved in 250 ml ofN,N-dimethylformamide and treated with 27.64 g (200 mmol) of potassiumcarbonate. At 100° C., 53.55 g (240 mmol) of tert-butylα-bromoisobutyrate are added dropwise. The mixture is stirred foranother hour, a further 200 mmol of potassium carbonate and 240 mmol oftert-butyl α-bromoisobutyrate are added and, after 4 hours at 100° C., 1l of water is added. Following extraction with diethyl ether, washingwith 1 N aqeuous sodium hydroxide solution and saturated sodium chloridesolution and drying over magnesium sulphate, the solvent is distilledoff and the residue is purified by flash chromatography on silica gel(cyclohexane→cyclohexane/ethyl acetate 20:1→10:1→5:1) and dried underreduced pressure. The target compound is obtained in the form ofcolourless crystals in a yield of 42%.

¹H-NMR (200 MHz, CDCl₃): δ=1.40 (s, 9H), 1.62 (s, 6H), 6.91 (d, 2H),7.79 (d, 2H), 9.88 (s, 1H).

MS (ESI): 265 [M+H]⁺.

The following compounds are obtained similarly to the procedure ofExample III-2:

EXAMPLE III-3 Ethyl 2-(4-formylphenoxy)-2-methylbutanoate

Yield: 11.71% ¹H-NMR (200 MHz, CDCl₃): δ=1.00 (t, 3H), 1.22 (t, 3H),1.61 (s, 3H), 1.90-2.20 (m, 2H), 4.24 (q, 2H), 6.90 (d, 2H), 7.80 (d,2H), 9.85 (s, 1H).

MS (ESI): 251 [M+H]⁺, 273 [M+Na]⁺.

EXAMPLE III-4 tert-Butyl 2-[(3-bromophenyl)sulphanyl]-2-methylpropanoat

Yield: 87%

¹H-NMR (200 MHz, CDCl₃): δ=1.43 (s, 9H), 1.45 (s, 6H), 7.14-7.28 (m,1H), 7.39-7.53 (m, 2H), 7.67 (t, 1H).

MS (DCI/NH₃): 348 [M+NH₄ ⁺].

EXAMPLE III-5 tert-Butyl 2-(3-formylphenoxy)-2-methylpropanoate

Yield: 35%

¹H-NMR (300 MHz, CDCl₃): δ=1.44 (s, 9H), 1.61 (s, 6H), 7.14 (dd, 1H),7.31-7.35 (m, 1H), 7.41 (t, 1H), 7.45-7.52 (m, 1H).

MS (DCI/NH₃): 282 [M+NH₄ ⁺].

EXAMPLE III-6 tert-Butyl 2-(3-bromophenoxy)-2-methylpropanoate

Yield: 21%

¹H-NMR (300 MHz, CDCl₃): δ=1.44 (s, 9H), 1.56 (s, 6H), 6.74-6.83 (m,1H), 7.00-7.04 (m, 1H), 7.06-7.11 (m, 2H).

MS (DCI/NH₃): 332 [M+NH₄ ⁺].

EXAMPLE III-7 tert-Butyl2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenoxy]-2-methylpropanoate

Yield: 24%

Melting point: 142-143° C.

EXAMPLE III-8 tert-Butyl2-[(3-formylphenyl)sulphanyl]-2-methylpropanoate

At −78° C., 30.00 g (90.56 mmol) of the compound from Example III-4 aredissolved in tetrahydrofuran and treated with 36.2 ml of a 2.5 Mn-butyllithium solution in hexane. 13.94 ml (181.12 mmol) ofN,N-dimethylformamide are then added. After 30 min, the mixture iswarmed to room temperature and stirred for 1 hour. 30 ml of 1 Nhydrochloric acid are added, the solvent is distilled off, the residueis extracted with ethyl acetate and the extract is washed with saturatedsodium bicarbonate solution and sodium chloride solution and then driedover magnesium sulphate. Following flash chromatography on silica gel(dichloromethane), the target compound is purified by NP-HPLC(cyclohexane/ethyl acetate) and obtained in a yield of 10%.

¹H-NMR (300 MHz, CDCl₃): δ=1.43 (s, 9H), 1.46 (s, 6H), 7.50 (t, 1H),7.77-7.80 (m, 1H), 7.87 (d, 1H), 7.98-8.05 (m, 1H), 10.00 (s, 1H).

MS (DCI/NH₃): 298 [M+NH₄ ⁺].

EXAMPLE III-9 tert-Butyl2-{3-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethenyl]phenoxy}-2-methyl-propanoate

In an autoclave, 14.93 g (47.37 mmol) of the compound from ExampleIII-6, 10.25 g (59.21 mmol) of vinylphthalimide, 0.39 g (1.27 mmol) oftris-o-tolylphosphine, 0.07 g (0.32 mmol) [lacuna] and 21.78 g (215.23mmol) of triethylamine are heated at 130° C. Water/methanol is added,and the precipitate is then filtered off with suction and recrystallizedfrom cyclohexane/ethyl acetate.

Yield: 66%.

¹H-NMR (200 MHz, CDCl₃): δ=1.40 (s, 9H), 1.50 (s, 6H), 6.73 (dd, 1H),6.86-6.93 (m, 1H), 7.16 (t, 1H), 7.21-7.34 (m, 2H), 7.43 (d, 1H),7.80-8.00 (m, 4H).

MS (DCI/NH₃): 425 [M+NH₄ ⁺].

EXAMPLE III-10 tert-Butyl2-{3-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]phenoxy}-2-methyl-propanoate

15.00 g (36.81 mmol) of the compound from Example III-9 are dissolved in200 ml of tetrahydrofuran and stirred overnight in a hydrogen atmosphereunder atmospheric pressure in the presence of a suspension of 2.00 g(2.16 mmol) of Wilkinson's catalyst in 40 ml of ethanol. Two flashchromatographies on silica gel (cyclohexane/dichloromethane10:1→cyclohexane/ethyl acetate 10:1→5:1 andcyclohexane→cyclohexane/dichloromethane→dichloromethane) give the titlecompound in a yield of 64%.

¹H-NMR (200 MHz, CDCl₃): δ=1.45 (s, 9H), 1.52 (s, 6H), 2.85-3.00 (m,2H), 3.82-3.95 (m, 2H), 6.65-6.80 (m, 2H), 6.88 (d, 1H), 7.15 (t, 1H),7.62-7.76 (m, 2H), 7.77-7.89 (m, 2H).

MS (ESI): 432 [M+Na⁺], 841 [2M+Na⁺].

EXAMPLE III-11 tert-Butyl 2-(4-aminophenoxy)-2-methylpropanoate

18.88 g (49.50 mmol) of the compound from Example III-7 are dissolved in25 ml of ethanol and, with 12.04 ml (247.49 mmol) of hydrazine hydrate,heated at the boil for 2 h and then stirred at room temperature for 12hours. The precipitate is separated off and washed with ethanol and thefiltrate is concentrated and then diluted with 1 l of diethyl ether.This solution is washed with 1 N sodium hydroxide solution and saturatedsodium chloride solution and dried over magnesium sulphate. The solventis removed, giving the title compound in a yield of 87%.

Melting point: 87-88° C.

The following compound is obtained similarly to the procedure of ExampleIII-11:

EXAMPLE III-12 tert-Butyl 2-[3-(2-aminoethyl)phenoxy]-2-methylpropanoate

Yield: 70%

¹H-NMR (200 MHz, CDCl₃): δ=1.31 (broad s, 2H), 1.44 (s, 9H), 1.56 (s,6H), 2.69 (t, 2H), 2.94 (t, 2H), 6.64-6.75 (m, 2H), 6.81 (d, 1H), 7.15(t, 1H).

MS (EI): 279 [M⁺].

EXAMPLE III-13 tert-Butyl2-(4-{[(2-furylmethyl)amino]methyl}phenoxy)-2-methylpropanoate

20.00 g (75.67 mmol) of the compound from Example III-2 and 7.35 g(75.67 mmol) of 2-furfurylamine are stirred at room temperature with24.06 g (113.50 mmol) of sodium triacetoxyborohydride in 350 ml of1,2-dichloroethane for 5 hours. Saturated sodium bicarbonate solutionand ethyl acetate are added to the reaction mixture. The organic phaseis dried over magnesium sulphate and the solvent is distilled off, andthe residue is then purified by flash chromatography on silica gel(cyclohexane→cyclohexane/ethyl acetate 10:1→2:1). The target compound isobtained in a yield of 72%.

¹H-NMR (200 MHz, CDCl₃): δ=1.61 (broad s, 1H), 1.44 (s, 9H), 1.55 (s,6H), 3.71 (s, 2H), 3.77 (s, 2H), 6.17 (d, 1H), 6.26-6.36 (m, 1H),6.70-6.88 (m, 2H), 7.18 (d, 2H), 7.32-7.40 (m, 1H).

MS (ESI): 346 [M+H]⁺.

EXAMPLE III-14 tert-Butyl2-{4-[(2-furylmethyl)amino]phenoxy}-2-methylpropanoate

4.79 g (19.06 mmol) of the compound from Example III-11 and 1.83 g(19.06 mmol) of furfural are dissolved in 80 ml of 1,2-dichloroethaneand, in the presence of 6.06 g (28.59 mmol) of sodiumtriacetoxyborohydride, stirred at room temperature for 5 hours.Saturated sodium bicarbonate solution and ethyl acetate are added to thereaction solution. The organic phase is dried over magnesium sulphateand the solvent is distilled off, and the residue is then purified byflash chromatography on silica gel (cyclohexane→cyclohexane/ethylacetate 10:1→2:1) and by NP-HPLC (cyclohexane/ethyl acetate 10:1). Thetarget compound is obtained in a yield of 79%.

¹H-NMR (200 MHz, CDCl₃): δ=1.46 (s, 9H), 1.48 (s, 6H), 3.80 (broad s,1H), 4.26 (s, 2H), 6.21 (d, 1H), 6.25-6.35 (m, 1H), 6.50-6.61 (m, 2H),6.72-6.85 (m, 2H), 7.30-7.39 (m, 1H).

MS (DCI/NH₃): 332 [M+H⁺], 349 [M+NH₄ ⁺].

EXAMPLE III-15 tert-Butyl2-[4-[[(2-ethoxy-2-oxoethyl)(2-furanylmethyl)amino]methyl]phenoxy]-2-methyl-propanoate

18.14 g (52.50 mmol) of the compound from Example III-13, 11 ml oftriethylamine and 1.10 g (2.97 mmol) of tetra-n-butylammonium iodide areinitially charged in 200 ml of tetrahydrofuran and treated with 8.77 ml(78.75 mmol) of ethyl bromoacetate, and the mixture is stirred at roomtempeature for 1 hour and at 60° C. for 2 hours. Water and ethyl acetateare then added to the mixture and the mixture is washed with saturatedsodium chloride solution and dried over magnesium sulphate, and, afterremoval of the solvent, the residue is purified by flash chromatographyon silica gel (cyclohexane/dichloromethane 4:1→cyclohexane/ethyl acetate10:1→5:1). The yield of target compound is quantitative.

¹H-NMR (300 MHz, CDCl₃): δ=1.26 (t, 3H), 1.43 (s, 9H), 1.55 (s, 6H),3.30 (s, 2H), 3.71 (s, 2H), 3.83 (s, 2H), 4.15 (q, 2H), 6.19 (d, 1H),6.28-6.34 (m, 1H), 6.77-6.85 (m, 2H), 7.22 (d, 2H), 7.35-7.41 (m, 1H).

MS (ESI): 432 [M+H]⁺.

EXAMPLE III-16 tert-Butyl2-[4-[[(carboxymethyl)(2-furanylmethyl)amino]methyl]phenoxy]-2-methyl-propanoate

22.01 g (51.00 mmol) of the compound from Example III-15 are stirred at80° C. in 785 ml of ethanol in the presence of 6.12 g (153.00 mmol) ofsodium hydroxide for 1 hour. The solvent is distilled off and water isadded, and the mixture is then acidified using 1 N hydrochloric acid andextracted with ethyl acetate. The extract is then washed with water andsaturated sodium chloride solution and dried over magnesium sulphate.The amount of solvent is reduced and the product is then filtered offwith suction and dried, giving the target compound in a yield of 74%.

Melting point: 152-155° C.

EXAMPLE III-172-Bromo-N-[4-isopropyl-2-(trifluoromethyl)phenyl]acetamide

50 g (246.06 mmol) of 4-isopropyl-2-(trifluoromethyl)aniline and 27.39 g(270.66 mmol) of triethylamine are initially charged in 1000 ml ofdichloromethane. At 0°-5° C., 54.63 g (270.66 mmol) of bromoacetylbromide, dissolved in 200 ml of dichloromethane, are added dropwise. Themixture is stirred at room temperature for 20 hours. The reactionmixture is then extracted successively with water, 1 N hydrochloricacid, water, saturated sodium bicarbonate solution and water. Theorganic phase is dried over sodium sulphate and the solvent is removedunder reduced pressure. The residue is purified chromatographically. Theproduct is recrystallized from cyclohexane/n-pentane, filtered off withsuction and dried under reduced pressure at 40° C. for 20 hours. Thisgives 32.45 g (41% of theory) of the title compound.

¹H-NMR (300 MHz, CDCl₃): δ=1.25 (d, 6H); 2.95 (sept., 1H); 4.05 (s, 2H);7.45 (d, 1H); 7.49 (s, 1H); 8.02 (d, 1H); 8.50 (br s, 1H).

EXAMPLE III-18 2-Bromo-N-(4-tert-butyl-2-methylphenyl)acetamide

5.5 g (33.69 mmol) of 4-tert-butyl-2-methylaniline and 3.75 g (37.06mmol) of triethylamine are initially charged in 150 ml ofdichloromethane. At 0°-5° C., 7.48 g (37.06 mmol) of bromoacetylbromide, dissolved in 90 ml of dichloromethane, are added dropwise, anda light-brown precipitate is formed. The mixture is stirred at roomtemperature overnight. 150 ml of ethyl acetate are then added to thereaction mixture, which is extracted successively with water, 1 Nhydrochloric acid, water, saturated sodium bicarbonate soluton andwater. The organic phase is dried over magnesium sulphate and freed fromthe solvent under reduced pressure. The residue is purifiedchromatographically. The product is recrystallized from ethyl acetateand n-pentane, filtered off with suction and dried under reducedpressure at 40° C. This gives 6.53 g (68% of theory) of the titlecompound.

¹H-NMR (400 MHz, CDCl₃): δ=1.3 (s, 9H); 2.3 (s, 3H); 4.06 (s, 2H);7.20-7.23 (m, 1H); 7.25 (d, 1H); 7.7 (d, 1H); 8.05 (br s, 1H).

EXAMPLE III-19 2-Bromo-N-(4-cyclohexyl-2-methylphenyl)acetamide

Yield: 41.0% of theory

¹H-NMR (200 MHz, CDCl₃): δ=1.20-1.50 (m, 5H); 1.65-1.95 (m, 5H); 2.28(s, 3H); 2.35-2.55 (m, 1H); 4.07 (s, 2H); 7.00-7.13 (m, 2H); 7.69 (d,1H); 8.05 (br s, 1H).

EXAMPLE III-20 2-Bromo-N-(5,6,7,8-tetrahydro-1-naphthalenyl)acetamide

Yield: 95.6% of theory

¹H-NMR (200 MHz, CDCl₃): δ=1.70-1.90 (m, 4H); 2.55-2.70 (m, 2H);2.75-2.85 (m, 2H); 4.08 (s, 2H); 6.95 (d, 1H); 7.14 (t, 1H); 7.69 (d,1H); 8.09 (br s, 1H).

EXAMPLE III-212-Bromo-N-[4-(1-naphthyloxy)-2-(trifluoromethyl)phenyl]acetamide

Yield: 80.5% of theory

¹H-NMR (200 MHz, CDCl₃): δ=4.08 (s, 2H); 7.01 (d, 1H); 7.18 (dd, 1H);7.30-7.62 (m, 4H); 7.70 (d, 1H); 7.85-8.17 (m, 3H); 8.47 (br s, 1H).

EXAMPLE III-22 2-Bromo-N-[5-chloro-2-(2-naphthyloxy)phenyl]acetamide

Yield: 77.9% of theory

¹H-NMR (200 MHz, CDCl₃): δ=3.99 (s, 2H); 6.88 (d, 1H); 7.06 (dd, 1H);7.21-7.36 (m, 2H); 7.38-7.57 (m, 2H); 7.68-7.79 (m, 1H); 7.80-7.95 (m,2H); 8.51 (d, 1H); 8.85 (br s, 1H).

EXAMPLE III-23 N-[2,4-Bis(trifluoromethyl)phenyl]-2-bromoacetamide

Yield: 28% of theory

¹H-NMR (200 MHz, CDCl₃): δ=4.10 (s, 2H); 7.80-7.91 (m, 2H); 8.50 (d,1H); 8.80 (br s, 1H).

EXAMPLE III-24 2-Bromo-N-(2-ethoxy-1-naphthyl)acetamide

Yield: 24% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.46 (t, 3H); 4.10-4.30 (m, 4H); 7.26-7.30(d, 1H); 7.36 (t, 1H); 7.50 (t, 1H); 7.70-7.87 (m, 3H); 8.07 (br s, 1H).

EXAMPLE III-252-Bromo-N-{5-[(ethylsulphonyl)methyl]-1-naphthyl}acetamide

Yield: 16% of theory

¹H-NMR (200 MHz, CDCl₃): δ=1.37 (t, 3H); 1.54 (s, 1H); 2.91 (q, 2H);4.20 (s, 2H); 4.72 (s, 2H); 7.53-7.70 (m, 3H); 7.90-8.11 (m, 3H); 8.65(br s, 1H).

EXAMPLE III-262-Bromo-N-[5-chloro-2-methyl-4-(trifluoromethoxy)phenyl]acetamide

Yield: 84.0% of theory

¹H-NMR (200 MHz, CDCl₃): δ=2.35 (s, 3H); 4.08 (s, 2H); 7.18 (s, 1H);8.05-8.20 (m, 2H).

EXAMPLE III-27 4-Methyl-1,3-oxazole-5-carbaldehyde oxime

0.50 g (4.50 mmol) of 4-methyl-1,3-oxazole-5-carbaldehyde [prepared fromthe corresponding alcohol (Chem. Ber. 1961, 1248) by Swern oxidation(Tetrahedron 34, 1651 (1978))] is initially charged in 3 ml of water andtreated with 0.66 g (9.45 mmol) of hydroxylamine hydrochloride in 2 mlof water. 0.68 g (4.95 mmol) of potassium carbonate is then added. After2 h, the mixture is filtered off with suction and the product is washedwith water and dried at room temperature. The yield is 0.41 g (72.2% oftheory).

¹H-NMR (200 MHz, DMSO): δ=2.21 (s, 3H); 8.20 (s, 1H); 8.33 (s, 1H);11.48 (s, 1H).

EXAMPLE III-28 (4-Methyl-1,3-oxazol-5-yl)methylamine

4.00 g (31.72 mmol) of 4-methyl-1,3-oxazole-5-carbaldehyde oxime areinitially charged in 70 ml of acetic acid. At room temperature, 47.70 g(729.50 mmol) of zinc dust are added in small portions. The mixture isstirred at room temperature for 2 hours and the zinc dust is thenfiltered off with suction and washed twice with 50 ml of acetic acid.Under reduced pressure, the filtrate is freed from the solvent. Theresidue is treated with 20% strength aqueous sodium hydroxide solutionuntil a pH of 11 is reached. During the addition, white crystalsprecipitate out. These are triturated with ethyl acetate and filteredoff with suction. Under reduced pressure, the combined filtrates arefreed from the solvent, and the residue is then purifiedchromatographically. This gives 1.34 g (38% of theory) of the titlecompound.

¹H-NMR (300 MHz, CDCl₃): δ=1.5 (s, 2H); 2.15 (s, 3H); 3.83 (s, 2H); 7.73(s, 1H).

EXAMPLE III-29 1,1-Dimethylethyl2-[(4-bromophenyl)thio]-2-ethyl-butanoate

The synthesis was carried out similarly to Example II-1 from4-bromothiophenol and 1,1-dimethylethyl 2-bromo-2-ethyl-butanoate[preparation, for example, similarly to Liebigs Ann. Chem. 725, 106-115(1969); J. Am. Chem. Soc. 77, 946-947 (1955), and bromination withN-bromosuccinimide or bromine, for example similarly to TetrahedronLett. 1970, 3431; J. Org. Chem. 40, 3420 (1975)].

Yield: 15.9% of theory

¹H-NMR (300 MHz, CDCl₃): δ=0.96 (t, 6H); 1.58-1.74 (m, 4H); 7.28-7.35(m, 2H); 7.39-7.46 (m, 2H).

EXAMPLE III-30 1,1-Dimethylethyl2-ethyl-2-[(4-formylphenyl)thio]-butanoate

The synthesis was carried out similarly to Example II-2 using thecompound from Example III-29 as starting material.

Yield: 70.4% of theory

¹H-NMR (300 MHz, CDCl₃): δ=0.96 (t, 6H); 1.64-1.87 (m, 4H); 7.60 (d,2H); 7.78 (d, 2H); 10.1 (s, 1H).

EXAMPLE III-31 tert-Butyl2-ethyl-2-[(4-{[(2-furylmethyl)amino]methyl}phenyl)-sulphanyl]butanoate

The synthesis was carried out similarly to Example III-13, using thecompound from Example III-30 and furfurylamine as starting materials.

Yield: 83.1% of theory

¹H-NMR (300 MHz, CDCl₃): δ=0.93 (t, 6H); 1.43 (s, 9H); 1.60-1.75 (m,4H); 3.78 (s, 4H); 6.18 (d, 1H); 6.28-6.35 (m, 1H); 7.25 (d, 2H);7.35-7.38 (m, 1H); 7.43 (d, 2H).

EXAMPLE III-32 tert-Butyl2-methyl-2-[4-({[(4-methyl-1,3-oxazol-5-yl)methyl]amino}methyl)-phenoxy]-propanoate

1.25 g (4.73 mmol) of tert-butyl 2-(4-formylphenoxy)-2-methylpropanoate(Example I-4) and 0.64 g (5.67 mmol) of(4-methyl-1,3-oxazol-5-yl)methylamine (Example III-28) are togetherinitially charged in 1,2-dichloroethane. At room temperature, 1.50 g(7.09 mmol) of sodium triacetoxyborohydride are added. The reactionmixture is stirred at room temperature for 4 hours and then admixed withsaturated sodium bicarbonate solution and extracted with ethyl acetate.The organic phase is dried over magnesium sulphate and freed from thesolvent under reduced pressure. The residue is purifiedchromatographically on silica gel (dichloromethane/methanol 30:1) andthen dried under reduced pressure. This gives 1.104 g (65% of theory) ofthe title compound.

¹H-NMR (200 MHz, CDCl₃): δ=1.45 (s, 9H); 1.55 (s, 6H); 2.11 (s, 3H);3.70 (s, 2H); 3.77 (s, 2H); 6.70-6.90 (m, 2H); 7.10-7.20 (m, 2H); 7.29(s, 1H); 7.75 (br s, 1H).

The following compounds were obtained similarly to the procedure ofExample III-32:

EXAMPLE III-33 tert-Butyl2-(4-{[(2-methoxyethyl)amino]methyl}phenoxy)-2-methylpropanoate

Yield: 92.8% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.44 (s, 9H); 1.55 (s, 6H); 2.48 (br s, 1H);2.83 (t, 2H); 3.35 (s, 3H); 3.54 (t, 2H); 3.77 (s, 2H); 6.75-6.86 (m,2H); 7.19 (d, 2H).

EXAMPLE III-34 tert-Butyl2-methyl-2-[4-({[(5-methyl-2-furyl)methyl]amino}methyl)-phenoxy]-propanoate

Yield: 55.1% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.44 (s, 9H); 1.55 (s, 6H); 2.27 (s, 3H);3.71 (s, 4H); 5.83-5.92 (m, 1H); 6.00-6.08 (m, 1H); 6.75-6.88 (m, 2H);7.12-7.24 (m, 2H).

EXAMPLE III-35 tert-Butyl2-[(4-{[(2-methoxyethyl)amino]methyl}phenyl)-sulphanyl]-2-methyl-propanoate

4.00 g (14.27 mmol) of tert-butyl2-[(4-formylphenyl)sulphanyl]-2-methylpropanoate (Example II-2) and 1.07g (14.27 mmol) of 2-methoxyethylamine are dissolved in 80 ml of1,2-dichloroethane and, after 30 min and after 10 hours, admixed with4.54 g (21.40 mmol) of sodium triacetoxyborohydride. The reaction ischecked by TLC, and ethyl acetate and saturated sodium bicarbonatesolution are then added and the product is extracted with ethyl acetate.The organic phase is washed with 1 N HCl and dried over magnesiumsulphate, and the product is, after distillative removal of the solvent,purified by silica gel chromatography (ethyl acetate/cyclohexane 1:1).

Yield: 2.69 g (55.6% of theory)

¹H-NMR (300 MHz, CDCl₃): δ=1.45 (s, 15H); 2.96 (t, 2H); 3.37 (s, 3H);3.72 (t, 2H); 4.13 (s, 2H); 7.52 (s, 4H).

The following compound was obtained similarly to the procedure ofExample III-35:

EXAMPLE III-36 tert-Butyl2-methyl-2-{[4-({[(4-methyl-1,3-oxazol-5-yl)methyl]amino}methyl)-phenyl]-sulphanyl}propanoate

Yield: 68.8% of theory

¹H-NMR (200 MHz, CDCl₃): δ=1.43 (s, 15H); 2.12 (s, 3H); 3.77 (s, 2H);3.78 (s, 2H); 7.22-7.33 (m, 2H); 7.46 (d, 2H); 7.75 (s, 1H).

WORKING EXAMPLES 3 Example 3-1 tert-Butyl2-[4-[[[2-[(2,4-dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)-amino]methyl]phenoxy]-2-methyl-propanoate

0.50 g (1.25 mmol) of the compound from Example III-16, 0.23 g (1.88mmol) of 2,4-dimethylaniline, 0.22 g (1.63 mmol) of1-hydroxy-1H-benzotriazole, 0.31 g (1.63 mmol) of EDCxHCl, 0.38 g (3.75mmol) of 4-methylmorpholine and 0.01 g (0.08 mmol) of4-dimethylaminopyridine are stirred in 30 ml of N,N-dimethylformamide at0° C. for 2 hours and then at room temperature overnight. Water is addedand the mixture is extracted with ethyl acetate, and the organic phasesare then washed with 1 N hydrochloric acid, water, saturated sodiumbicarbonate solution and saturated sodium chloride solution and thendried over magnesium sulphate. The solvent is distilled off and theresidue is purified by flash chromatography on silica gel(cyclohexane/dichloroethane 2:1→cyclohexane/ethyl acetate 10:1→4:1).Recrystallization from n-heptane gives the target compound in a yield of78%.

Melting point: 90-91° C.

Example 3-2 tert-Butyl2-[4-[[[2-[(2,4-dimethylphenyl)methylamino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenoxy]-2-methyl-propanoate

At 0° C., 0.51 g (1.00 mmol) of the compound from Example 3-1 and 0.04 g(1.10 mmol) of sodium hydride are stirred for 30 min and then admixedwith 0.07 ml (1.10 mmol) of iodomethane and then with water. The mixtureis extracted with ethyl acetate, the extract is washed with water andsaturated sodium chloride solution and dried over magnesium sulphate,the solvent is distilled off and the residue is purified by flashchromatography on silica gel (cyclohexane/dichloromethane3:1→dichloromethane→dichloromethane/ethyl acetate 15:1).Recrystallization from n-pentane gives the target compound in a yield of51%.

Melting point: 80-81° C.

Example 3-3 tert-Butyl2-[4-[[[2-[(2,4-dimethylphenyl)amino]ethyl](2-furanylmethyl)-amino]methyl]phenoxy]-2-methyl-propanoate

In 5 ml toluene, 0.25 g (0.50 mmol) of the compound from Example 3-1 istreated with 0.30 ml of 2 M borane-dimethyl sulphide solution intetrahydrofuran, and the mixture is heated at the boil for 2 hours. Themixture is then stirred in the presence of 5 ml of 2 N sodium carbonatesolution for 1 hour and the organic phase is washed with water and withsaturated sodium chloride solution. The organic phase is dried overmagnesium sulphate and the solvent is distilled off, and the residue isthen purified using silica gel flash chromatography(cyclohexane/dichloromethane 3:1→cyclohexane/ethyl acetate 10:1). Thisgives the target compound in a yield of 37%.

¹H-NMR (200 MHz, CDCl₃): δ=1.43 (s, 9H), 1.55 (s, 6H), 2.15 (s, 3H),2.22 (s, 3H), 2.73-2.87 (m, 2H), 3.09-3.22 (m, 2H); 3.57 (s, 2H), 3.63(s, 2H), 6.12-6.19 (m, 1H), 6.28-6.35 (m, 1H), 6.47 (d, 1H), 6.73-6.95(m, 4H), 7.20 (d, 1H), 7.34-7.40(m, 1H).

MS (ESI): 493 [M+H]⁺, 985 [2M+H]⁺.

Example 3-42-[4-[[[2-[(2,4-Dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenoxy]-2-methyl-propionicacid

7.09 g (14.00 mmol) of the compound from Example 3-1 and 35 ml oftrifluoroacetic acid are stirred at room temperature in 35 ml ofdichloromethane for 2 hours. The solvent is distilled off and theresidue is then dissolved in ethyl acetate, washed with water, 20percent strength sodium acetate solution and saturated sodium chloridesolution and then dried over magnesium sulphate. The solvent is removedand the residue is then purified by flash chromatography on silica gel(dichloromethane→dichloromethane/ethyl acetate 5:1→2:1→1:1): The givesthe target compound in a yield of 82%.

¹H-NMR (200 MHz, CDCl₃): δ=1.57 (s, 6H), 2.24 (s, 3H), 2.27 (s, 3H),3.31 (s, 2H), 3.67 (s, 2H), 3.75 (s, 2H), 6.22-6.36 (m, 2H), 6.88 (d,2H), 6.93-7.03 (m, 2H), 7.23 (d, 2H), 7.34-7.40 (m, 1H), 7.78 (d, 1H),8.00 (broad s, 1H), 9,09 (s, 1H).

MS (ESI): 451 [M+H]⁺, 901 [2M+H]⁺.

The following compounds are obtained similarly to the procedure ofExample 3-4:

Example 3-52-[4-[[[2-[(2,4-Dimethylphenyl)methylamino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenoxy]-2-methyl-propionicacid

Yield: 85%

¹H-NMR (200 MHz, CDCl₃): δ=1.46 (s, 6H), 1.92 (s, 3H), 2.24 (s, 3H),2.73 (q, 2H), 3.00 (s, 3H), 3.30 (broad s, 1H), 3.63 (d, 2H), 3.78 (d,2H), 6.19 (d, 1H), 6.30-6.40 (m, 1H), 6.74 (d, 2H), 6.80-7.10 (m, 5H),7.52-7.57 (m, 1H).

MS (ESI): 465 [M+H]⁺, 487 [M+Na]⁺.

Example 3-62-[4-[[[2-[(2,4-Diimethylphenyl)amino]ethyl](2-furanylmethyl)amino]-methyl]phenoxy]-2-methyl-propionicacid

Yield: 60%

¹H-NMR (200 MHz, DMSO-d₆): δ=1.49 (s, 6H), 2.01 (s, 3H), 2.12 (s, 3H),2.55-2.72 (broad m, 2H), 2.97-3.20 (broad m, 2H), 3.46-3.78 (m, 4H),4.40 (broad s, 1H), 6.20-6.50 (m, 3H), 6.68-6.88 (m, 4H), 7.12-7.30 (m,2H), 7.56-7.68 (m, 1H), 13.00 (broad s, 1H).

MS (ESI): 437 [M+H]⁺, 873 [2M+H]⁺.

Example 3-7 1,1-Dimethylethyl2-[4-[[(2-methoxyethyl)[2-[[4-(1-methylethyl)-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl]amino]methyl]phenoxy]-2-methyl-propionate

0.533 g (1.65 mmol) of tert-butyl2-(4-{[(2-methoxyethyl)amino]methyl}phenoxy)-2-methylpropanoate (ExampleIII-33) is initially charged in 6 ml of dimethylformamide. At roomtemperature, 0.588 g (1.81 mmol) of2-bromo-N-[4-isopropyl-2-(trifluoromethyl)phenyl]acetamide (ExampleIII-17) and 0.152 g (1.81 mmol) of sodium bicarbonate are added. Themixture is set at 90° C. for 2 hours. The reaction mixture is thenallowed to cool, and water is added. The mixture is extracted once withethyl acetate and the organic phase is washed three times with water andonce with saturated sodium chloride solution. The organic phase is driedover sodium sulphate and freed from the solvent under reduced pressure.The residue is purified chromatographically on silica gel(cyclohexane/ethyl acetate 4:1) and the product is then dried underreduced pressure. This gives 0.885 g (95% of theory) of the titlecompound.

¹H-NMR (400 MHz, CDCl₃): δ=1.25 (d, 6H); 1.42 (s, 9H); 1.55 (s, 6H);2.80 (t, 2H); 2.93 (sept., 1H); 3.28 (s, 3H); 3.30 (s, 2H); 3.54 (t,2H); 3.70 (s, 2H); 6.80 (d, 2H); 7.20 (d, 2H); 7.39 (dd, 1H); 7.45 (d,1H); 8.17 (d, 1H); 9.65 (br s, 1H).

Example 3-82-[4-[[(2-Methoxyethyl)[2-[[4-(1-methylethyl)-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl]amino]methyl]phenoxy]-2-methyl-propionicacid

0.842 g (1.49 mmol) of the compound from Example 3-7 is initiallycharged in 10 ml of dichloromethane. At room temperature, 10 ml oftrifluoroacetic acid are added. The reaction mixture is stirred at roomtemperature for 2 hours. The mixture is then concentrated under reducedpressure using a rotary evaporator. The residue is taken up in ethylacetate and washed with water, 20% strength sodium acetate solution,water and saturated sodium chloride solution. The organic phase is driedover magnesium sulphate and freed from the solvent under reducedpressure. The product is purified chromatographically on silica gel(dichloromethane/methanol 30:1) and then dried under reduced pressure.This gives 0.648 g (85% of theory) of the title compound.

¹H-NMR (200 MHz, CDCl₃): δ=1.26 (d, 6H); 1.55 (s, 6H); 2.81 (t, 2H);2.91 (sept., 1H); 3.28 (s, 3H); 3.31 (s, 2H); 3.55 (t, 2H); 3.72 (s,2H); 6.90 (d, 2H); 7.25 (d, 2H); 7.35-7.49 (m, 2H); 8.12 (d, 1H); 9.62(br s, 1H).

Example 3-92-[4-[[(2-Methoxyethyl)[2-[[4-(1-methylethyl)-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl]amino]methyl]phenoxy]-2-methyl-propionicacid hydrochloride

0.4 g (0.78 mmol) of the compound from Example 3-7 are dissolved in 4 mlof ethyl acetate. At 40° C., first 8 ml of 1N hydrochloric acid (indiethyl ether) and then 12 ml of diethyl ether are added. The mixture isallowed to stand at 4° C. for one hour. The precipitated crystals arefiltered off with suction, washed with a mixture of ethyl acetate anddiethyl ether (ratio 1:1) and then dried at 40° C. under reducedpressure for 20 hours. This gives 0.362 g (84.5% of theory) of the titlecompound.

¹H-NMR (200 MHz, DMSO): δ=1.22 (d, 6H); 1.55 (s, 6H); 2.94-3.08 (m, 1H);3.28 (s, 3H); 3.30-3.40 (m, 2H); 3.60-3.80 (m, 2H); 4.00-4.20 (m, 2H);4.30-4.50 (m, 2H); 6.86 (d, 2H); 7.20-7.70 (m, 5H); 10.25 (br s, 1H);13.18 (br s, 1H).

Example 3-10 1,1-Dimethylethyl2-[4-[[[2-[(4-cyclohexyl-2-methylphenyl)amino]-2-oxoethyl](2-methoxyethyl)-amino]methyl]phenoxy]-2-methyl-propionate

0.303 g (0.94 mmol) of tert-butyl2-(4-{[(2-methoxyethyl)amino]methyl}phenoxy)-2-methylpropanoate (ExampleIII-33) is initially charged in 5 ml of dimethylformamide. At roomtemperature, 0.319 g (1.03 mmol) of2-bromo-N-(4-cyclohexyl-2-methylphenyl)acetamide (Example III-19) and0.086 g (1.03 mmol) of sodium bicarbonate are added. The mixture isstirred at 90° C. for 2 hours. The reaction mixture is then allowed tocool, and water is added. The mixture is extracted with ethyl acetateand the organic phase is washed with water and saturated sodium chloridesolution. The organic phase is dried over sodium sulphate and freed fromthe solvent under reduced pressure. The residue is purifiedchromatographically on silica gel (cyclohexane/ethyl acetate 3:1) andthe product is dried under reduced pressure. This gives 0.464 g (90% oftheory) of the title compound.

¹H-NMR (300 MHz, CDCl₃): δ=1.20-1.45 (m, 14H); 1.50 (s, 6H); 1.70-1.90(m, 5H); 2.25 (s, 3H); 2.36-2.48 (m, 1H); 2.80 (t, 2H); 3.25 (s, 5H);3.5 (t, 2H); 3.69 (s, 2H); 6.80 (d, 2H); 6.98-7.06 (m, 2H); 7.15-7.25(m, 2H); 7.85 (d, 1H); 9.25 (br s, 1H).

Example 3-112-[4-[[[2-[(4-Cyclohexyl-2-methylphenyl)amino]-2-oxoethyl](2-methoxyethyl)-amino]methyl]phenoxy]-2-methyl-propionicacid hydrochloride

0.398 g (0.72 mmol) of the compound from Example 3-10 is initiallycharged in 5 ml of dichloromethane. At room temperature, 5 ml oftrifluoroacetic acid are added. The reaction mixture is stirred at roomtemperature for 2 hours. The mixture is then concentrated under reducedpressure using a rotary evaporator. The residue is taken up in ethylacetate and washed with water, 20% strength sodium acetate solution,water and saturated sodium chloride solution. The organic phase is driedover magnesium sulphate and freed from the solvent under reducedpressure. The product is purified chromatographically on silica gel(dichloromethane/methanol 30:1). With heating, the residue is dissolvedin dichloromethane, 1N hydrochloric acid in diethyl ether is added andn-heptane is added dropwise until the mixture becomes slightly turbid.The product is filtered off with suction, washed with diethyl ether anddried at 40° C. under reduced pressure. This gives 0.187 g (49% oftheory) of the title compound.

¹H-NMR (300 MHz, CDCl₃): δ=1.15-1.47 (m, 5H); 1.55 (s, 6H); 1.68-1.90(m, 5H); 2.25 (s, 3H); 2.36-2.49 (m, 1H); 2.85 (t, 2H); 3.28 (s, 3H);3.30 (s, 2H); 3.52 (t, 2H); 3.72 (s, 2H); 6.87 (d, 2H); 6.99-7.10 (m,2H); 7.25 (d, 2H); 7.80 (d, 1H); 9.25 (br s, 1H).

The following compounds were obtained similarly to the procedure ofExamples 3-7 and 3-10:

Example 3-12 1,1-Dimethylethyl2-[4-[[[2-[[2,4-bis(trifluoromethyl)phenyl]amino]-2-oxoethyl][(5-methyl-2-furanyl)-methyl]amino]methyl]phenoxy]-2-methyl-propionate

Yield: 88% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (s, 9H); 1.55 (s, 6H); 2.15 (s, 3H);3.30 (s, 2H); 3.65 (s, 4H); 5.85 (m, 1H); 6.12 (d, 1H); 6.81 (m, 2H);7.20 (m, 2H); 7.25 (m, 1H); 7.35 (s, 1H); 8.57 (d, 1H); 9.85 (br s, 1H).

Example 3-13 1,1-Dimethylethyl2-[[4-[[[2-[[5-chloro-2-methyl-4-(trifluoromethoxy)phenyl]-amino]-2-oxoethyl][(4-methyl-5-oxazolyl)methyl]amino]methyl]phenyl]thio]-2-methyl-propionoate

Yield: 80.2% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (s, 9H); 1.41 (s, 6H); 2.14 (s, 3H);2.29 (s, 3H); 3.32 (s, 2H); 3.73 (s, 2H); 3.77 (s, 2H); 7.13 (s, 1H);7.23-7.31 (m, 2H); 7.49 (d, 2H); 7.78 (s, 1H); 8.30 (s, 1H); 9.05 (s,1H).

Example 3-14 1,1-Dimethyl-ethyl2-[[4-[[[2-[[5-chloro-2-methyl-4-(trifluoromethoxy)phenyl]-amino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenyl]thio]-2-methyl-propionate

Yield: 85.1% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.39 (s, 9H); 1.41 (s, 6H); 2.30 (s, 3H);3.31 (s, 2H); 3.74 (s, 4H); 6.28 (d, 1H); 6.31-6.35 (m, 1H); 7.12 (s,1H); 7.27 (d, 2H); 7.35-7.38 (m, 1H); 7.48 (d, 2H); 8.31 (s, 1H); 9.19(s, 1H).

Example 3-15 1,1-Dimethylethyl2-[[4-[[[2-[(2,4-dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]-methyl]phenyl]thio]-2-ethyl-butanoate

Yield: 73.4% of theory

¹H-NMR (200 MHz, CDCl₃): δ=0.95 (t, 6H); 1.41 (s, 9H); 1.55-1.78 (m,4H); 2.26 (s, 3H); 2.28 (s, 3H); 3.30 (s, 2H); 3.73 (s, 2H); 3.74 (s,2H); 6.20-6.38 (m, 2H); 6.90-7.08 (m, 2H); 7.28 (d, 2H); 7.35-7.50 (m,3H); 7.75-7.88 (m, 1H); 9.05 (s, 1H).

Example 3-16 1,1-Dimethylethyl2-[[4-[[[2-[(4-cyclohexyl-2-methylphenyl)amino]-2-oxoethyl](2-methoxyethyl)-amino]methyl]phenyl]thio]-2-methyl-propionoate

Yield: 81.9% of theory

¹H-NMR (200 MHz, CDCl₃): δ=1.31-1.47 (m, 18H); 1.70-1.95 (m, 6H);2.20-2.31 (m, 4H); 2.35-2.51 (m, 1H); 2.82 (t, 2H); 3.28 (s, 5H); 3.51(t, 2H); 3.77 (s, 2H); 7.03 (d, 2H); 7.31 (d, 2H); 7.46 (d, 2H); 7.83(d, 1H); 9.24 (s, 1H).

Example 3-17 1,1-Dimethylethyl2-[[4-[[[2-[[4-(1,1-dimethylethyl)-2-methylphenyl]amino]-2-oxoethyl](2-methoxy-ethyl)amino]methyl]phenyl]thio]-2-methyl-propionate

Yield: 82.9% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.29 (s, 12H); 1.40 (s, 9H); 1.42 (s, 6H);2.82 (t, 2H); 3.29 (s, 5H); 3.51 (t, 2H); 3.77 (s, 2H); 7.13-7.40 (m,4H); 7.40-7.53 (m, 2H); 7.86 (d, 1H); 9.26 (br s, 1H).

Example 3-18 1,1-Dimethylethyl2-[[4-[[[2-[[5-chloro-2-methyl-4-(trifluoromethoxy)phenyl]-amino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenyl]thio]-2-ethyl-butanoate

Yield: 86.8% of theory

¹H-NMR (200 MHz, CDCl₃): δ=0.94 (t, 6H); 1.41 (s, 9H); 1.55-1.75 (m,4H); 2.30 (s, 3H); 3.31 (s, 2H); 3.73 (s, 2H); 3.75 (s, 2H); 6.24-6.38(m, 2H); 7.12 (s, 1H); 7.26 (d, 2H); 7.36 (d, 1H); 7.44 (d, 2H); 8.31(s, 1H); 9.19 (s, 1H).

Example 3-19 1,1-Dimethylethyl2-[[4-[[[2-[[5-chloro-2-methyl-4-(trifluoromethoxy)phenyl]-amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]phenyl]thio]-2-methyl-propionate

Yield: 57.4% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (s, 9H); 1.41 (s, 6H); 2.29 (s, 3H);2.83 (t, 2H); 3.27 (s, 3H); 3.29 (s, 2H); 3.51 (t, 2H); 3.77 (s, 2H);7.11 (s, 1H); 7.30 (d, 2H); 7.46 (d, 2H); 8.29 (s, 1H); 9.44 (s, 1H).

Example 3-20 1,1-Dimethylethyl2-methyl-2-[4-[[[2-[[4-(1-methylethyl)-2-(trifluoromethyl)-phenyl]amino]-2-oxoethyl][(5-methyl-2-furanyl)methyl]amino]methyl]phenoxy]-propionate

Yield: 94% of theory

¹H-NMR (400 MHz, CDCl₃): δ=1.25 (d, 6H); 1.40 (s, 9H); 1.55 (s, 6H);2.17 (s, 3H); 2.88 (sept., 1H); 3.25 (s, 2H); 3.15 (m, 4H); 5.85 (m,1H); 6.10 (d, 1H); 6.81 (d, 2H); 7.21 (d, 2H); 7.35 (m, 1H); 7.43 (m,1H); 8.15 (d, 1H); 9.67 (s, 1H).

Example 3-21 1,1-Dimethylethyl2-[4-[[[2-[(2-ethoxy-1-naphthalenyl)amino]-2-oxoethyl][(5-methyl-2-furanyl)-methyl]amino]methyl]phenoxy]-2-methyl-propionate

Yield: 95% of theory

¹H-NMR (200 MHz, CDCl₃): δ=1.30 (t, 3H); 1.43 (s, 9H); 1.54 (s, 6H);2.25 (s, 3H); 3.44 (s, 2H); 3.78-3.82 (m, 4H); 4.15 (q, 2H); 5.89-5.94(m, 1H); 6.15-6.18 (m, 1H); 6.84 (d, 2H); 7.20-7.38 (m, 4H); 7.45 (t,1H); 7.65 (d, 1H); 7.75-7.85 (m, 2H); 9.05 (br s, 1H).

Example 3-22 1,1-Dimethylethyl2-methyl-2-[4-[[[(5-methyl-2-furanyl)methyl][2-oxo-2-[(5,6,7,8-tetrahydro-1-naphthalenyl)amino]ethyl]amino]methyl]phenoxy]-propionate

Yield: 91% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (s, 9H); 1.55 (s, 6H); 1.70-1.95 (m,4H); 2.20 (s, 3H); 2.65-2.82 (m, 4H); 3.24 (s, 2H); 3.67 (s, 4H);5.86-5.90 (m, 1H); 6.10-6.14 (d, 1H); 6.78-6.93 (m, 3H); 7.08 (t, 1H);7.22 (d, 2H); 7.89 (d, 1H); 9.20 (br s, 1H).

Example 3-23 1,1-Dimethylethyl2-[4-[[[2-[(2,4-dichlorophenyl)amino]-2-oxoethyl](2-methoxy-ethyl)amino]methyl]-phenoxy]-2-methyl-propionate

Yield: 87% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.39 (s, 9H); 1.53 (s, 6H); 2.81 (t, 2H);3.24 (s, 3H); 3.29 (s, 2H); 3.51 (t, 2H); 3.70 (s, 2H); 6.80 (m, 2H);7.10-7.30 (m, 3H); 7.38 (d, 1H); 8.42 (d, 1H); 9.93 (br s, 1H).

Example 3-24 1,1-Dimethylethyl2-[4-[[(2-methoxyethyl)[2-[[4-(1-naphthalenyloxy)-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl]amino]methyl]phenoxy]-2-methyl-propionate

Yield: 95.5% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1:41 (s, 9H); 1.55 (s, 6H); 2.80 (t, 2H);3.28 (s, 3H); 3.30 (s, 2H); 3.54 (t, 2H); 3.70 (s, 2H); 6.80 (d, 2H);6.95 (d, 1H); 7.13-7.25 (m, 3H); 7.34 (d, 1H); 7.40 (t, 1H); 7.47-7.58(m, 2H); 7.66 (d, 1H); 7.89 (dd, 1H); 8.07-8.21 (m, 2H); 9.68 (br s,1H).

Example 3-25 1,1-Dimethylethyl2-[4-[[[2-[[5-[(ethylsulphonyl)methyl]-1-naphthalenyl]amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]phenoxy]-2-methyl-propionate

Yield: 91% of theory

¹H-NMR (200 MHz, CDCl₃): δ=1.20-1.37 (m, 12H); 1.55 (s, 6H); 2.83-2.94(m, 4H); 3.22 (s, 3H); 3.39 (s, 2H); 3.55 (t, 2H); 3.77 (s, 2H); 4.77(s, 2H); 6.81 (d, 2H); 7.15-7.30 (m, 2H); 7.50-7.70 (m, 3H); 7.91 (d,1H); 8.12 (d, 1H); 8.22 (d, 1H); 10.18 (br s, 1H).

Example 3-26 1,1-Dimethylethyl2-methyl-2-[4-[[[2-[[4-(1-methylethyl)-2-(trifluoromethyl)-phenyl]amino]-2-oxoethyl][(4-methyl-5-oxazolyl)methyl]amino]methyl]phenoxy]-propionate

Yield: 83.5% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.25 (d, 6H); 1.40 (s, 9H); 1.55 (s, 6H);2.10 (s, 3H); 2.85-3.00 (sept., 1H); 3.28 (s, 2H); 3.66 (s, 2H); 3.75(s, 2H); 6.82 (d, 2H); 7.20 (d, 2H); 7.38 (dd, 1H); 7.40-7.45 (m, 1H);7.75 (s, 1H); 8.14 (d, 1H); 9.45 (br s, 1H).

Example 3-27 1,1-Dimethylethyl2-[4-[[[2-[[2,4-bis(trifluoromethyl)phenyl]amino]-2-oxoethyl][(4-methyl-5-oxazolyl)-methyl]amino]methyl]phenoxy]-2-methyl-propionate

Yield: 79.5% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (s, 9H); 1.55 (s, 6H); 2.11 (s, 3H);3.30 (s, 2H); 3.68 (s, 2H); 3.76 (s, 2H); 6.81 (d, 2H); 7.18 (d, 2H);7.70-7.80 (m, 2H); 7.86 (s, 1H); 8.56 (d, 1H); 9.71 (br s, 1H).

Example 3-28 1,1-Dimethylethyl2-[4-[[[2-[[4-(1,1-dimethylethyl)-2-methylphenyl]amino]-2-oxoethyl](2-methoxy-ethyl)amino]methyl]phenoxy]-2-methyl-propionate

Yield: 81% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.30 (s, 9H); 1.40 (s, 9H); 1.55 (s, 6H);2.38 (s, 3H); 2.80 (t, 2H); 3.29 (s, 5H); 3.50 (t, 2H); 3.70 (s, 2H);6.80 (d, 2H); 7.15-7.25 (m, 4H); 7.78 (d, 1H); 9.30 (br s, 1H).

Example 3-29 1,1-Dimethylethyl2-[4-[[[2-[[2,4-bis(trifluoromethyl)phenyl]amino]-2-oxoethyl](2-methoxyethyl)-amino]methyl]phenoxy]-2-methyl-propionate

Yield: 80% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.39 (s, 9H); 1.55 (s, 6H); 2.82 (t, 2H);3.28 (s, 3H); 3.33 (s, 2H); 3.52 (t, 2H); 3.71 (s, 2H); 6.80 (d, 2H);7.18 (d, 2H); 7.78 (d, 1H); 7.84 (s, 1H); 8.60 (d, 1H); 9.98 (br s, 1H).

Example 3-30 1,1-Dimethylethyl2-[4-[[[2-[[2,4-bis(trifluoromethyl)phenyl]amino]-2-oxoethyl](2-furanylmethyl)-amino]methyl]phenoxy]-2-methyl-propionate

Yield: 84% of theory

¹H-NR (300 MHz, CDCl₃): δ=1.40 (s, 9H); 1.55 (s, 6H); 3.30 (s, 2H); 3.65(s, 2H); 3.75 (s, 2H); 6.20-6.30 (m, 1H); 6.30-6.38 (m, 1H); 6.82 (d,2H); 7.18 (d, 2H); 7.36-7.39 (m, 1H); 7.75 (d, 1H); 7.90 (s, 1H); 8.60(d, 1H); 9.82 (br s, 1H).

Example 3-31 1,1-Dimethylethyl2-[[4-[[[2-[[2,4-bis(trifluoromethyl)phenyl]amino]-2-oxoethyl](2-furanylmethyl)-amino]methyl]phenyl]thio]-2-methyl-propionate

Yield: 92% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.40 (s, 9H); 1.45 (s, 6H); 3.31 (s, 2H);3.74-3.80 (m, 4H); 6.25 (d, 1H); 6.30-6.38 (m, 1H); 7.22-7.40 (m, 3H);7.50 (d, 2H); 7.78 (d, 1H); 7.90 (s, 1H); 8.61 (d, 1H); 9.78 (br s, 1H).

The following compounds were obtained similarly to the procedure ofExample 3-8:

Example 3-322-[4-[[[2-[[2,4-Bis(trifluoromethyl)phenyl]amino]-2-oxoethyl][(5-methyl-2-furanyl)-methyl]amino]methyl]phenoxy]-2-methyl-propionicacid

Yield: 83.4% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.56 (s, 6H); 2.15 (s, 3H); 3.29 (s, 2H);3.69 (s, 2H); 3.71 (s, 2H); 5.80-5.88 (m, 1H); 6.13 (d, 1H); 6.89-6.98(m, 2H); 7.20-7.35 (m, 2H); 7.74 (d, 1H); 7.86 (s, 1H); 8.56 (d, 1H);9.79 (s, 1H).

Example 3-332-[[4-[[[2-[[5-Chloro-2-methyl-4-(trifluoromethoxy)phenyl]amino]-2-oxoethyl][(4-methyl-5-oxazolyl)methyl]amino]methyl]phenyl]thio]-2-methyl-propionicacid

Yield: 62.8% of theory

¹H-NMR (200 MHz, CDCl₃): δ=1.47 (s, 6H); 2.11 (s, 3H); 2.28 (s, 3H);3.35 (s, 2H); 3.74 (s, 2H); 3.77 (s, 2H); 7.11 (s, 1H); 7.20-7.30 (m,2H); 7.49 (d, 2H); 7.80 (s, 1H); 8.28 (s, 1H); 9.04 (s, 1H).

Example 3-342-[[4-[[[2-[[5-Chloro-2-methyl-4-(trifluoromethoxy)phenyl]amino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenyl]thio]-2-methyl-propionicacid

Yield: 90.9% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.46 (s, 6H); 2.28 (s, 3H); 3.32 (s, 2H);3.75 (s, 4H); 6.30 (dd, 2H); 7.10 (s, 1H); 7.29 (d, 2H); 7.36 (d, 1H);7.48 (d, 2H); 8.27 (s, 1H); 9.16 (s, 1H).

Example 3-352-[[4-[[[2-[(2,4-Dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]-methyl]phenyl]thio]-2-ethyl-butanoicacid

Yield: 96.6% of theory

¹H-NMR (300 MHz, CDCl₃): δ=0.97 (t, 6H); 1.60-1.90 (m, 4H); 2.25 (s,3H); 2.28 (s, 3H); 3.31 (s, 2H); 3.73 (s, 2H); 3.74 (s, 2H); 6.26 (d,1H); 6.29-6.35 (m, 1H); 6.95-7.05 (m, 2H); 7.29 (d, 2H); 7.37 (d, 1H);7.46 (d, 2H); 7.80 (d, 1H); 9.03 (s, 1H).

Example 3-362-[[4-[[[2-[[5-Chloro-2-methyl-4-(trifluoromethoxy)phenyl]amino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenyl]thio]-2-ethyl-butanoicacid

Yield: 90.9% of theory

¹H-NMR (300 MHz, CDCl₃): δ=0.96 (t, 6 H); 1.58-1.87 (m, 4H); 2.28 (s,3H); 3.31 (s, 2H); 3.73 (s, 2H); 3.76 (s, 2H); 6.26 (d, 1H); 6.30-6.36(m, 1H); 7.10 (s, 1H); 7.27 (d, 2H); 7.34-7.40 (m, 1H); 7.45 (d, 2H);8.28 (s, 1H); 9.16 (s, 1H).

Example 3-372-[[4-[[[2-[[5-Chloro-2-methyl-4-(trifluoromethoxy)phenyl]amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]phenyl]thio]-2-methyl-propionicacid

Yield: 83.9% of theory

¹H-NMR (200 MHz, CDCl₃): δ=1.46 (s, 6H); 2.27 (s, 3H); 2.84 (t, 2H);3.27 (s, 3H); 3.31 (s, 2H); 3.50 (t, 2H); 3.77 (s, 2H); 7.10 (br s, 1H);7.31 (d, 2H); 7.48 (d, 2H); 8.24 (s, 1H); 9.43 (s, 1H).

Example 3-382-Methyl-2-[4-[[[2-[[4-(1-methylethyl)-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl][(5-methyl-2-furanyl)methyl]amino]methyl]phenoxy]-propionicacid

Yield: 91% of theory

¹H-NMR (200 MHz, CDCl₃): δ=1.25 (d, 6H); 1.55 (s, 6H); 2.17 (s, 3H);2.91 (sept., 1H); 3.28 (s, 2H); 3.7 (s, 4H); 5.80-5.90 (m, 1H); 6.13 (d,1H); 6.90 (m, 2H); 7.17-7.30 (m, 2H); 7.32-7.47 (m, 2H); 8.12 (d, 1H);9.55 (br s, 1H).

Example 3-392-[4-[[[2-[(2-Ethoxy-1-naphthalenyl)amino]-2-oxoethyl][(5-methyl-2-furanyl)-methyl]amino]methyl]phenoxy]-2-methyl-propionicacid

Yield: 64% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.25-1.32 (t, 3H); 1.60 (s, 3H); 2.25 (s,3H); 3.45 (s, 2H); 3.82 (s, 4H); 4.15 (quart., 2H); 5.94 (m, 1H); 6.17(d, 1H); 6.90-7.00 (m, 2H); 7.23-7.46 (m, 5H); 7.60-7.70 (m, 1H);7.75-7.80 (m, 2H); 9.05 (br s, 1H).

Example 3-402-Methyl-2-[4-[[[(5-methyl-2-furanyl)-methyl][2-oxo-2-[(5,6,7,8-tetrahydro-1-naphthalenyl)amino]ethyl]amino]methyl]phenoxy]-propionicacid

Yield: 76% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.55 (s, 6H); 1.75-1.95 (m, 4H); 2.20 (s,3H); 2.36 (t, 2H); 2.78 (t, 2H); 3.30 (s, 2H); 3.69 (s, 4H); 5.89 (m,1H); 6.12 (d, 1H); 6.83-6.94 (m, 4H); 7.09 (t, 1H); 7.20-7.32 (m, 1H);7.85 (d, 1H); 9.15 (s, 1H).

Example 3-412-[4-[[[2-[(2,4-Dichlorophenyl)amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]phenoxy]-2-methyl-propionicacid

Yield: 69% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.55 (s, 6H); 2.82 (t, 2H); 3.28 (s, 3H);3.00 (s, 2H); 3.54 (t, 2H); 3.75 (s, 2H); 6.90 (m, 2H); 7.18-7.36. (m,3H); 7.39 (d, 1H); 8.40 (d, 1H); 9.90 (br s, 1H).

Example 3-422-[4-[[(2-Methoxyethyl)[2-[[4-(1-naphthalenyloxy)-2-(trifluoromethyl)phenyl]-amino]-2-oxoethyl]amino]methyl]phenoxy]-2-methyl-propionicacid

Yield: 74% of theory

¹H-NMR (300 MHz, DMSO): δ=1.45 (s, 6H); 2.72 (t, 2H); 3.18 (s, 3H); 3.25(s, 2H); 3.47 (t, 2H); 3.68 (s, 2H); 6.78 (d, 2H); 7.10 (d, 1H); 7.21(d, 2H); 7.28 (dd, 1H); 7.40 (d, 1H); 7.48-7.66 (m, 3H); 7.80 (d, 1H);7.90 (d, 1H); 8.05 (t, 2H); 9.60 (br s, 1H).

Example 3-432-[4-[[[2-[[5-[(Ethylsulphonyl)methyl]-1-naphthalenyl]amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]phenoxy]-2-methyl-propionicacid

Yield: 40.5% of theory

¹H-NMR (400 MHz, CD₂Cl₂): δ=1.34 (t, 3H); 1.46 (s, 6H); 2.83-3.04 (m,4H); 3.24 (s, 3H); 3.37 (s, 2H); 3.32-3.64 (m, 2H); 3.78 (s, 2H); 4.72(s, 2H); 6.83 (d, 2H); 7.31 (d, 2H); 7.46-7.65 (m, 3H); 7.90 (d, 1H);8.04-8.20 (m, 2H); 10.10 (br s, 1H).

Example 3-442-Methyl-2-[4-[[[2-[[4-(1-methylethyl)-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl][(4-methyl-5-oxazolyl)methyl]amino]methyl]phenoxy]-propionicacid

Yield: 69% of theory

¹H-NMR (200 MHz, CDCl₃): δ=1.25 (d, 6H); 1.58 (s, 6H); 2.09 (s, 3H);2.82-3.04 (sept., 1H); 3.30 (s, 2H); 3.66 (s, 2H); 3.76 (s, 2H); 6.90(d, 2H); 7.25 (d, 2H); 7.35-7.48 (m, 2H); 7.80 (s, 1H); 8.11 (d, 1H);9.40 (brs, 1H).

Example 3-452-[4-[[[2-[[2,4-Bis(trifluoromethyl)phenyl]amino]-2-oxoethyl][(4-methyl-5-oxazolyl)methyl]amino]methyl]phenoxy]-2-methyl-propionicacid

Yield: 76% of theory

¹H-NMR (200 MHz, CDCl₃): δ=1.60 (s, 6H); 2.10 (s, 3H); 3.32 (s, 2H);3.70 (s, 2H); 3.77 (s, 2H); 6.90 (d, 2H); 7.21 (d, 2H); 7.73-7.90 (m,3H); 8.55 (d, 1H); 9.68 (br s, 1H).

Example 3-462-[4-[[[2-[[2,4-Bis(trifluoromethyl)phenyl]amino]-2-oxoethyl](2-methoxyethyl)-amino]methyl]phenoxy]-2-methyl-propionicacid

Yield: 77% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.55 (s, 6H); 2.84 (t, 2H); 3.25 (s, 3H);3.35 (s, 2H); 3.55 (t, 2H); 3.75 (s, 2H); 6.90 (d, 2H); 7.15-7.30 (m,2H); 7.75 (d, 1H); 7.88 (s, 1H); 8.59 (d, 1H); 9.91 (br s, 1H).

Example 3-472-[4-[[[2-[[2,4-Bis(trifluoromethyl)phenyl]amino]-2-oxoethyl](2-furanylmethyl)-amino]methyl]phenoxy]-2-methyl-propionicacid

Yield: 91% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.57 (s, 6H); 3.30 (s, 2H); 3.70 (s, 2H);3.77 (s, 2H); 6.30 (dd, 2H); 6.88 (d, 2H); 7.20-7.35 (m, 2H); 7.37-7.42(m, 1H); 7.75 (d, 1H); 7.86 (s, 1H); 8.56 (d, 1H); 9.80 (br s, 1H).

Example 3-482-[[4-[[[2-[[2,4-Bis(trifluoromethyl)phenyl]amino]-2-oxocthyl](2-furanylmethyl)-amino]methyl]phenyl]thio]-2-methyl-propionicacid

Yield: 91% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.46 (s, 6H); 3.32 (s, 2H); 3.75 (s, 4H);6.25 (dd, 2H); 7.20-7.40 (m, 3H); 7.50 (d, 214); 7.78 (d, 1H); 7.90 (s,1H); 8.59 (d, 1H); 9.78 (br s, 1H).

The following compounds were obtained similarly to the procedure ofExamples 3-9 and 3-11:

Example 3-492-[[4-[[[2-[(4-Cyclohexyl-2-methylphenyl)amino]-2-oxoethyl](2-methoxyethyl)-amino]methyl]phenyl]thio]-2-methyl-propionicacid hydrochloride

Yield: 53.3% of theory

¹H-NMR (300 MHz, DMSO): δ=1.20-1.48 (m, 12H); 1.62-1.87 (m, 5H); 2.14(s, 3H); 3.27 (s, 3H); 3.51 (br s, 2H); 3.74 (br s, 2H); 4.12 (br s,2H); 4.51 (br s, 2H); 7.02 (d, 2H); 7.16-7.30 (br s, 1H); 7.46-7.68 (m,4H); 9.93 (br s, 1H); 10.36 (br s, 1H); 12.74 (br s, 1H).

Example 3-502-[[4-[[[2-[[4-(1,1-Dimethylethyl)-2-methylphenyl]amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]phenyl]thio]-2-methyl-propionicacid hydrochloride

Yield: 85.3% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.29 (s, 9H); 1.56 (s, 6H); 2.26 (s, 3H);2.86 (t, 2H); 3.29 (s, 3H); 3.35 (s, 2H); 3.53 (t, 2H); 3.74 (s, 2H);6.88 (d, 2H); 7.15-7.26 (m, 4H); 7.79 (d, 1H); 9.26 (s, 1H).

Example 3-512-Methyl-2-[4-[[[2-[[4-(1-methylethyl)-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl][(5-methyl-2-furanyl)methyl]amino]methyl]phenoxy]-propionicacid hydrochloride

Yield: 99% of theory

¹H-NMR (300 MHz, DMSO): δ=1.20 (d, 6H); 1.50 (s, 6H); 2.27 (br s, 3H);2.96-3.05 (sept., 1H); 3.95 (br s, 2H); 4.31 (br s, 4H); 6.17 (br s,1H); 6.63 (br s, 1H); 6.85 (d, 2H); 7.46-7.57 (m, 5H); 10.23 (br s, 1H);10.55 (br s, 1H); 13.15 (br s, 1H).

Example 3-522-[4-[[[2-[[4-(1,1-Dimethylethyl)-2-methylphenyl]amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]phenoxy]-2-methyl-propionicacid hydrochloride

Yield: 54% of theory

LC-MS: 470 [M⁺]

Example 3-532-[4-[[[2-[(2,4-Dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenoxy]-2-methyl-propionicacid sodium salt

0.015 g (0.03 mmol) of the compound from Example 3-4 is dissolved in 0.5ml of ethanol and treated with 0.3 ml of 1N aqueous sodium hydroxidesolution. The reaction mixture is stirred for another 5 min and thenconcentrated using a rotary evaporator. The residue is taken up in alittle toluene and the solvent is removed under reduced pressure. Theproduct is then dried under reduced pressure for 20 hours. This gives0.015 g (95.5% of theory) of the title compound.

¹H-NMR (200 MHz, CDCl₃): δ=1.21 (s, 6H); 2.10-2.20 (m, 6H); 3.16 (s,2H); 3.58-3.64 (m, 4H); 6.18-6.25 (m, 2H); 6.73-6.82 (m, 2H); 7.09-7.35(m, 3H); 7.71 (d, 1H); 9.00 (br s, 1H).

The following compounds were obtained similarly to the procedure ofExamples 3-7 and 3-10:

Example 3-54 1,1-Dimethylethyl2-[[4-[[[2-[[4-(1-methylethyl)-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]phenyl]thio]-2-methyl-propionate

Yield: 61% of theory

¹H-NMR (200 MHz, CDCl₃): δ=1.24 (d, 6H); 1.39 (s, 9H); 1.42 (s, 6H);2.80 (t, 2H); 2.90-3.1 (m, 1H); 3.28 (s, 3H); 3.32 (s, 2H); 3.53 (t,2H); 3.78 (s, 2H); 7.25-7.50 (m, 6H); 8.14 (d, 1H); 9.62 (br s, 1H).

Example 3-55 1,1-Dimethylethyl2-methyl-2-[[4-[[[2-[[4-(1-methylethyl)-2-(trifluoromethyl)phenyl]amino]-2-oxo-ethyl][(4-methyl-5-oxazolyl)methyl]amino]methyl]phenyl]thio]propionate

Yield: 66% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.25 (d, 6H); 1.40 (s, 9H); 1.43 (s, 6H);2.10 (s, 3H); 2.90-3.10 (m, 1H); 3.29 (s, 2H); 3.70-3.80 (m, 4H);7.30-7.55 (m, 6H); 7.77 (s, 1H); 8.13 (d, 1H); 9.40 (br s, 1H).

Example 3-56 1,1-Dimethylethyl2-[[4-[[[2-[(2-methyl-4-methoxyphenyl)amino]-2-oxoethyl][(4-methyl-5-oxazolyl)-methyl]amino]methyl]phenyl]thio]-2-methyl-propionate

Yield: 86% of theory

¹H-NMR (200 MHz, CDCl₃): δ=1.41 (s, 9H); 1.43 (s, 9H); 2.13 (s, 3H);2.24 (s, 3H); 3.31 (s, 2H); 3.70-3.81 (m, 7H); 6.68-6.80 (m, 2H); 7.30(d, 2H); 7.50 (d, 2H); 7.67-7.75 (m, 1H); 7.78 (s, 1H); 8.80 (br s, 1H).

Example 3-57 1,1-Dimethyl-ethyl2-[[4-[[[2-[[2,4-bis(trifluoromethyl)phenyl]amino]-2-oxoethyl][(4-methyl-5-oxazolyl)methyl]amino]methyl]phenyl]thio]-2-methyl-propionate

Yield: 84% of theory

¹H-NMR (200 MHz, CDCl₃): δ=1.40 (s, 9H); 1.42 (s, 6H); 2.11 (s, 3H);3.32 (s, 2H); 3.74-3.82 (m, 4H); 7.29 (d, 2H); 7.49 (d, 2H); 7.70-7.85(m, 2H); 7.87 (s, 1H); 8.57 (d, 1H); 9.67 (br s, 1H).

Example 3-58 1,1-Dimethylethyl2-[4-[[[2-[(4-cyclohexyl-2-methylphenyl)amino]-2-oxoethyl][(4-methyl-5-oxazolyl)-methyl]amino]methyl]phenoxy]-2-methyl-propionate

Yield: 54.8% of theory

¹H-NMR (200 MHz, CDCl₃): δ=1.30-1.46 (m, 14H); 1.55 (s, 6H); 1.62-1.94(m, 6H); 2.12 (s, 3H); 2.26 (s, 3H); 3.29 (s, 2H); 3.65 (s, 2H); 3.74(s, 2H); 6.82 (d, 2H); 6.98-7.08 (m, 2H); 7.18 (d, 2H); 7.77 (s, 1H);7.83 (d, 1H); 8.96 (br s, 1H).

Example 3-59 1,1-Dimethyl-ethyl2-[4-[[[2-[[4-(1,1-dimethylethyl)-2-methylphenyl]amino]-2-oxoethyl][(4-methyl-5-oxazolyl)methyl]amino]methyl]phenoxy]-2-methyl-propionate

Yield: 64.7% of theory ¹H-NMR (200 MHz, CDCl₃): δ=1.29 (s, 9H); 1.41 (s,9H); 1.55 (s, 6H); 2.12 (s, 3H); 2.28 (s, 3H); 3.29 (s, 2H); 3.65 (s,2H); 3.75 (s, 2H); 6.82 (d, 2H); 7.10-7.30 (m, 4H); 7.77 (s, 1H); 7.85(d, 1H); 8.98 (br s, 1H).

Example 3-602-[[4-[[[2-[[4-(1-Methylethyl)-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl](2-methoxyethyl)amino]methyl]phenyl]thio]-2-methyl-propionicacid

0.248 g (0.43 mmol) of the compound from Example 3-54 is initiallycharged in 5 ml of dichloromethane. At room temperature, 5 ml oftrifluoroacetic acid are added. The reaction mixture is stirred at roomtemperature for 2 hours and then concentrated under reduced pressureusing a rotary evaporator. The residue is taken up in ethyl acetate andextracted with water, 20% strength sodium acetate solution, water andsaturated sodium chloride solution. The organic phase is dried overmagnesium sulphate and freed from the solvent under reduced pressure.The product is purified chromatographically on silica gel(dichloromethane, dichloromethane/methanol 30:1) and then dried underreduced pressure. This gives 197 mg (88% of theory) of the titlecompound.

¹H-NMR (200 MHz, CDCl₃): δ=1.25 (d, 6H); 1.49 (s, 6H); 2.80 (t, 2H);2.85-3.00 (m, 1H); 3.30 (s, 3H); 3.32 (s, 2H); 3.49-3.59 (m, 2H); 3.80(s, 2H); 7.24-7.53 (m, 6H); 8.12 (d, 1H); 9.58 (br s, 1H).

The following compounds were obtained similarly to the procedure ofExample 3-60:

Example 3-612-Methyl-2-[[4-[[[2-[[4-(1-methylethyl)-2-(trifluoromethyl)phenyl]amino]-2-oxoethyl][(4-methyl-5-oxazolyl)methyl]amino]methyl]phenyl]thio]-propionicacid

Yield: 81% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.25 (d, 6H); 1.50 (s, 6H); 2.07 (s, 3H);2.85-3.00 (m, 1H); 3.39 (s, 2H); 3.74-3.78 (m, 4H); 7.30 (d, 2H);7.36-7.53 (m, 4H); 7.79 (s, 1H); 8.11 (d, 1H); 9.39 (br s, 1H).

Example 3-622-[[4-[[[2-[(2-Methyl-4-methoxyphenyl)amino]-2-oxoethyl][(4-methyl-5-oxazolyl)methyl]amino]methyl]phenyl]thio]-2-methyl-propionicacid

Yield: 84% of theory

¹H-NMR (200 MHz, CDCl₃): δ=1.51 (s, 6H); 2.08 (s, 3H); 2.23 (s, 3H);3.35 (s, 2H); 3.70-3.82 (m, 7H); 6.70-6.80 (m, 2H); 7.28 (d, 2H); 7.48(d, 2H); 7.63-7.73 (m, 1H); 7.80 (s, 1H); 8.81 (br s, 1H).

Example 3-632-[[4-[[[2-[[2,4-Bis(trifluoromethyl)phenyl]amino]-2-oxoethyl][(4-methyl-5-oxazolyl)methyl]amino]methyl]phenyl]thio]-2-methyl-propionicacid

Yield: 76% of theory

¹H-NMR (300 MHz, CDCl₃): δ=1.49 (s, 6H); 2.09 (s, 3H); 3.35 (s, 2H);3.74-3.80 (m, 4H); 7.29 (d, 2H); 7.49 (d, 2H); 7.75-7.82 (m, 2H); 7.87(s, 1H); 8.56 (d, 1H); 9.66 (br S, 1H).

Example 3-642-[4-[[[2-[(4-Cyclohexyl-2-methylphenyl)amino]-2-oxoethyl][(4-methyl-5-oxazolyl)methyl]amino]methyl]phenoxy]-2-methyl-propionicacid

Yield: 80% of theory

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=2.64 min([M+H]⁺=534).

Example 3-652-[4-[[[2-[[4-(1,1-Dimethylethyl)-2-methylphenyl]amino]-2-oxoethyl][(4-methyl-5-oxazolyl)methyl]amino]methyl]phenoxy]-2-methyl-propionicacid

Yield: 80% of theory

LC-MS: Acetonitrile/30% aqueous HCl/water (gradient): R_(t)=2.43 min([M+H]⁺=508).

WORKING EXAMPLES 4 Example 4-12-[4-[[[2-[(2,5-Dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]methyl]phenoxy]-2-methyl-propanoicacid

Step a)

Wang resin (from Rapp Polymere, Order No. H 1011) (48.0 g, 14.06 mmol ofreactive groups) is suspended in dichloromethane.2-(4-Formylphenoxy)-2-methyl-propionic acid [G. J. Ellymes, C. Glynis,J. Chem. Soc. Perkin Trans. 2, 1993, 43-48] (8.78 g, 42.18 mmol),diisopropylcarbodiimide (10.65 g, 84.35 mmol) and DMAP (3.44 g, 28.12mmol) are added, and the mixture is then shaken at room temperature for18 h. The mixture is then filtered and the resin is washed withdichloromethane, DMF and methanol, giving resin A.

Step b)

Resin A (2.50 g, 0.72 mmol of reactive groups) and 2-furfurylamine (352mg, 3.62 mmol) are suspended in 20 ml of trimethyl orthoformate. Themixture is shaken at room temperature for 20 h and then filtered, andthe resin is washed with DMF. The resin is then suspended in 20 ml ofDMF, tetrabutylammonium borohydride (559 mg, 2.17 mmol) and acetic acid(0.42 ml, 7.25 mmol) are added and the mixture is shaken at roomtemperature for 7 h. The mixture is then filtered and the resin iswashed with dichloromethane, DMF and methanol, giving resin B1.

Step c)

Resin B1(2.5 g, 0.72 mmol of reactive groups) is suspended in 40 ml ofdioxane and treated with triethylamine (3.03 ml, 21.75 mmol) andtrimethylsilyl bromoacetate (2.38 ml, 14.5 mmol). The mixture is shakenat 60° C. overnight. The mixture is then filtered and the resin iswashed with dichloromethane, DMF and methanol. The protective silylgroup is removed by suspending the resin in 25 ml of dioxane andtreating it with tetrabutylammonium fluoride solution (1 M in THF, 1ml). The mixture is shaken at room temperature for 1 h and thenfiltered. The resin is then washed with dichloromethane, DMF andmethanol, giving resin C1.

Step d)

Resin C1 (2.5 g, 0.72 mmol of reactive groups) is suspended in 20 ml ofDMF and treated with diisopropylethylamine (656 mg, 5.08 mmol), HATU(1.38 g, 3.63 mmol) and 2,5-dimethylaniline (615 mg, 5.08 mmol). Themixture is shaken at room temperature for 18 h and then filtered, andthe resin is washed with dichloromethane, DMF and methanol. The resin isthen suspended in a mixture of dichloromethane and trifluoroacetic acid.The mixture is shaken at room temperature for 30 min and then filteredand evaporated. The target compound is obtained as a colourless film.

LC-MS: R_(t)=3.68 min; [M+H]⁺=451.3 (100%), [M−H]⁺=449.3 (100%) [Method:Symmetry C18 column (Waters), flow rate: 0.5 ml/min, oven temp. 40° C.,pressure 400 bar, gradient: t=0 min: 10% A, 90% B; t=4.0 min: 90% A, 10%B; t=6.0 min: 90% A, 10% B; t=6.1 min 10% A, 90% B; t=7.5 min 10% A, 90%B. A: CH₃CN+0.1% HCOOH; B: H₂O+0.1% HCOOH].

¹H-NMR (d₆-DMSO): δ=1.4 (s, 6H), 2.3 (s, 3H), 2.4 (s, 3H), 3.3 (s, 2H),3.7 (s, 2H), 3.8 (s, 2H), 6.3 (d, 1H), 6.4 (d, 1H), 6.8 (d, 1H), 6.9 (d,2H), 7.05 (d, 1H), 7.2 (m, 2H), 7.4 (s, 1H), 7.8 (s, 1H).

Example 4-22-[4-[[[2-[(4-Methoxy-2,5-dimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)amino]-methyl]phenoxy]-2-methyl-propanoicacid

Resin C1 from Example 4-1 step c) (2.5 g, 0.72 mmol of reactive groups)is suspended in 20 ml of DMF and treated with diisopropylethylamine (656mg, 5.08 mmol), HATU (1.38 g, 3.63 mmol) and2,5-dimethyl-4-methoxyaniline (756 mg, 5.08 mmol). The mixture is shakenat room temperature for 18 h and then filtered, and the resin is washedwith dichloromethane, DMF and methanol. The resin is then suspended in amixture of dichloromethane and trifluoroacetic acid. The mixture isshaken at room temperature for 30 min and then filtered and evaporated.The target compound is obtained as a colourless film.

LC-MS: R_(t)=3.48 min; [M+H]⁺=481.226 (100%), [M−H]⁺=479.226 (100%)[Method: Symmetry C18 column (Waters), flow rate: 0.5 ml/min, oven temp.40° C., pressure 400 bar, gradient: t=0 min: 10% A, 90% B; t=4.0 min:90% A, 10% B; t=6.0 min: 90% A, 10% B; t=6.1 min 10% A, 90% B; t=7.5 min10% A, 90% B. A: CH₃CN+0.1% HCOOH; B: H₂O+0.1% HCOOH].

Example 4-32-[4-[[[2-[(4-Methoxy-2,5-dimethylphenyl)amino]-2-oxoethyl](2-thienylmethyl)amino]-methyl]phenoxy]-2-methyl-propanoicacid

Step a)

Resin A from Example 4-1 step a) (2.50 g, 0.72 mmol of reactive groups)and 2-aminomethylthiophene (409 mg, 3.62 mmol) are suspended in 20 ml oftrimethyl orthoformate. The mixture is shaken at room temperatureovernight and then filtered, and the resin is washed with DMF. The resinis then suspended in 20 ml of DMF, treated with tetrabutylammoniumborohydride (559 mg, 2.17 mmol) and acetic acid (0.42 ml, 7.25 mmol) andshaken at room temperature for 7 h. The mixture is then filtered and theresin is washed with dichloromethane, DMF and methanol, giving resin B2.

Step b)

Resin B2 (2.5 g, 0.72 mmol of reactive groups) is suspended in 40 ml ofdioxane and treated with triethylamine (3.03 ml, 21.75 mmol) andtrimethylsilyl bromoacetate (2.38 ml, 14.5 mmol). The mixture is shakenat 60° C. overnight. The mixture is then filtered and the resin iswashed with dichloromethane, DMF and methanol. The protective silylgroup is removed by suspending the resin in 25 ml of dioxane andtreating it with tetrabutylammonium fluoride solution (1 M in THF, 1ml). The mixture is shaken at room temperature for 1 h and thenfiltered. The resin is then washed with dichloromethane, DMF andmethanol, giving resin C2.

Step c)

Resin C2 (2.5 g, 0.72 mmol of reactive groups) is suspended in 20 ml ofDMF and treated with diisopropylethylamine (656 mg, 5.08 mmol), HATU(1.38 g, 3.63 mmol) and 2,5-dimethyl-4-methoxyaniline (657 mg, 5.08mmol). The mixture is shaken at room temperature for 18 h and thenfiltered, and the resin is washed with dichloromethane, DMF andmethanol. The resin is then suspended in a mixture of dichloromethaneand trifluoroacetic acid. The mixture is shaken at room temperature for30 min and then filtered and evaporated. The target compound is obtainedas a colourless film.

LC-MS: R_(t)=3.90 min; [M+H]⁺=497.4 (100%), [M−H]⁺=495.4 (100%) [Method:Symmetry C18 column (Waters), flow rate: 0.5 mil/min, oven temp. 40° C.,pressure 400 bar, gradient: t=0 min: 10% A, 90% B; t=4.0 min: 90% A, 10%B; t=6.0 min: 90% A, 10% B; t=6.1 min 10% A, 90% B; t=7.5 min 10% A, 90%B. A: CH₃CN+0.1% HCOOH; B: H₂O+0.1% HCOOH].

¹H-NMR (d₆-DMSO): δ=1.5 (s, 6H), 2.1 (s, 3H), 2.2 (s, 3H), 3.3 (s, 2H),3.7 (s, 2H), 3.8 (s, 3H), 4.0 (s, 2H), 6.8-7.5 (m, 9H).

The following compound is obtained in a similar manner:

Example 4-42-[4-[[[2-[(4-Methoxy-2,5-dimethylphenyl)amino]-2-oxoethyl][(5-methyl-2-furanyl)methyl]-amino]methyl]phenoxy]-2-methyl-propanoicacid

LC-MS: R_(t)=2.76 min; [M+H]⁺=495 (100%), [M−H]⁺=493 (100%) [Method:Symmetry C18 column (Waters), flow rate: 0.5 ml/min, oven temp. 40° C.,pressure 400 bar, gradient: t=0 min: 10% A, 90% B; t=4.0 min: 90% A, 10%B; t=6.0 min: 90% A, 10% B; t=6.1 min 10% A, 90% B; t=7.5 min 10% A, 90%B. A: CH₃CN+0.1% HCOOH; B: H₂O+0.1% HCOOH].

Example A Cellular Transactivation Assay

Test principle:

A cellular assay is used to identify activators of the peroxisomeproliferator-activated receptor alpha (PPAR-alpha).

Since mammalian cells contain different endogenous nuclear receptorswhich may complicate an unambiguous interpretation of the results, anestablished chimera system is used in which the ligand binding domain ofthe human PPARα receptor is fused to the DNA binding domain of the yeasttranscription factor GAL4. The resulting GAL4-PPARα chimera isco-transfected and stably expressed in CHO cells having a reporterconstruct.

Cloning:

The GAL4-PPARα expression construct contains the ligand binding domainof PPARα: (amino acids 167-468), which is PCR-amplified and cloned intothe vector pcDNA3.1. This vector already contains the GAL4 DNA bindingdomain (amino acids 1-147) of the vector pFC2-dbd (Stratagene). Thereporter construct, which contains five copies of the GAL4 binding siteupstream of a thymidine kinase promoter, expresses firefly luciferase(Photinus pyralis) following activation and binding of GAL4-PPARα.

Transactivation assay (luciferase reporter):

CHO (chinese hamster ovary) cells are sown in DMEM/F12 medium(BioWhittaker), supplemented by 10% foetal calf serum, 1%penicillin/streptomycin (GIBCO), at a cell density of 2×10³ cells perwell in a 384 well plate (Greiner). The cells are cultivated at 37° C.for 48 h and then stimulated. To this end, the substances to be testedare taken up in CHO-A-SFM medium (GIBCO), supplemented by 10% foetalcalf serum, 1% penicillin/streptomycin (GIBCO) and added to the cells.After a stimulation period of 24 hours, the luciferase activity ismeasured using a video camera. The relative light units measured give,as a function of the substrate concentration, a sigmoidal stimulationcurve. The EC₅₀ values are calculated using the computer programmeGraphPad PRISM (Version 3.02).

In this test, the compounds according to the invention of Examples 3-4,3-6, 3-60, 1-9, 2-7 and 2-12 show EC₅₀ values of from 0.04 to 200 nM.

Example B Determination of Fibrinogen

To determine the effect on the plasma fibrinogen concentration, maleWistar rats are treated with the substance to be examined for a periodof 4-9 days, by administration via a stomach tube or by mixing thesubstance with the feed. In terminal anaesthesia, citrated blood is thenobtained by heart puncture. The plasma fibrinogen levels are determinedusing the Clauss method [Clauss A., Acta Haenzatol. 17, 237-46 (1957)]by measuring the thrombin time using human fibrinogen as standard. Insome cases, parallel determinations are carried out using aturbidometric method [Becker U., Bartl K., Wahlefeld A. W., ThrombosisRes. 35, 475-84 (1984)] where batroxobin is used instead of thrombin.

Example C

Description of the test for finding pharmacologically active substanceswhich increase apoprotein A1 (ApoA1) and HDL cholesterol (HDL-C)concentrations in the serum of transgenic mice transfected with thehuman ApoA1 gene (hApoA1):

The substances to be examined in vivo for their HDL-C-increasingactivity are administered orally to male transgenic hApoA1 mice. One dayprior to the start of the experiment, the animals are randomized intogroups with the same number of animals, generally n=7-10. During theentire experiment, the animals have drinking water and feed ad libitum.The substances are administered orally once a day for 7 days. To thisend, the test substances are dissolved in a solution of Solutol HS15+ethanol+saline (0.9%) in a ratio of 1+1+8 or in a solution of SolutolHS 15+saline (0.9%) in a ratio of 2+8. The dissolved substances areadministered in a volume of 10 ml/kg of body weight using a stomachtube. Animals which have been treated in exactly the same manner buthave only been given the solvent (10 ml/kg of body weight), without testsubstance, serve as control group.

Prior to the first administration of substance, a blood sample from eachof the mice is taken by puncture of the retroorbital venous plexus, todetermine ApoA1, serum cholesterol, HDL-C and serum triglycerides (TG)(zero value). Subsequently, using a stomach tube, the test substance isadministered for the first time to the animals. 24 hours after the lastadministration of substance (on day 8 after the start of the treatment),another blood sample is taken from each animal by puncture of theretroorbital venous plexus, to determine the same parameters. The bloodsamples are centrifuged and, after the serum has been obtained,cholesterol and TG are determined photometrically using an EPOS Analyzer5060 (Eppendorf-Gerätebau, Netheler & Hinz GmbH, Hamburg). The saiddeterminations are carried out using commercial enzyme tests (BoehringerMannheim, Mannheim).

To determine the HDL-C, the non-HDL-C fraction is precipitated using 20%PEG 8000 in 0.2 M glycine buffer pH 10. From the supernatant, thecholesterol is determined UV-photometrically (BIO-TEK Instruments Inc.USA) in a 96-well plate using a commercial reagent (Ecoline 25, Merck,Darmstadt).

Human mouse ApoA1 is determined with a Sandwich ELISA method using apolyclonal antihuman ApoA1 and a monoclonal antihuman ApoA1 antibody(Biodesign International, USA). Quantification is carried outUV-photometrically (BIO-TEK Instruments, USA) using peroxidase-coupledanti-mouse-IGG antibodies (KPL, USA) and peroxidase substrate (KPL,USA).

The effect of the test substances on the HDL-C concentration isdetermined by subtracting the value measured for the 1^(st) blood sample(zero value) from the value measured for the 2^(nd) blood sample (afterthe treatment). The mean of the differences of all HDL-C values of onegroup is determined and compared to the mean of the differences of thecontrol group.

Statistical evaluation is carried out using student's t-test, after thevariances have been checked for homogeneity.

Substances which increase the HDL-C of the, treated animals in astatistically significant (p<0.05) manner by at least 20%, compared tothe control group, are considered to be pharmacologically effective.

What is claimed is:
 1. Compounds of the general formula (1)

in which A represents a bond or represents a —CH₂— or —CH₂CH₂— group, X represents O, S or CH₂, R¹, R² and R³ are identical or different and independently of one another each represents hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, hydroxyl, (C₁-C₆)-alkoxy, (C₆-C₁₀)-aryloxy, halogen, trifluoromethyl, trifluoromethoxy, (C₁-C₆)-alkylaminosulphonyl, nitro or cyano, or R¹ and R² are attached to two adjacent carbon atoms and together with these form a fused cyclohexane or benzene ring, the latter optionally being substituted by a (C₁-C₄)—alkylsulphonylmethyl group, and R³ is as defined above, R⁴ represents hydrogen or (C₁-C₄)-alkyl, R⁵ and R⁶ together with the carbon atom to which they are attached form a carbonyl group, R⁷ represents hydrogen, (C₁-C₆)-alkyl, phenyl or benzyl, where the aromatic radicals mentioned for their part may in each case be mono- to trisubstituted by identical or different substituents from the group consisting of (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, hydroxyl and halogen, R⁸ represents oxazolylmethyl which may be mono- to trisubstituted by identical or different substituents selected from the group consisting of halogen, hydroxyl, (C₁₋₆) alkyl, trifluoromethyl, trifluoromethoxy, cyano, nitro and amino, R⁹ and R¹⁰ are identical or different and independently of one another each represents hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, trifluoromethyl, trifluoromethoxy or halogen, R¹¹ and R¹² are identical or different and independently of one another each represents hydrogen or (C₁-C₆)-alkyl or together with the carbon atom to which they are attached form a (C₄-C₇)-cycloalkyl ring, and R¹³ represents hydrogen, and their pharmaceutically acceptable salts, hydrates and solvates.
 2. Compounds of the general formula (I) according to claim 1, in which A represents a bond or represents a —CH₂— or —CH₂CH₂— group, X represents O, S or CH₂, R¹, R² and R³ are identical or different and independently of one another each represents hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, nitro or cyano, R⁴ represents hydrogen or (C₁-C₄-alkyl, R⁵ and R⁶ together with the carbon atom to which they are attached form a carbonyl group, R⁷ represents hydrogen, (C₁-C₆)-alkyl, phenyl or benzyl, in which the aromatic radicals mentioned for their part may in each case be mono- to trisubstituted by identical or different substituents from the group consisting of (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, hydroxyl and halogen, R⁸ represents oxazolylmethyl which may be mono- to trisubstituted by identical or different substituents selected from the group consisting of halogen, hydroxyl, (C₁₋₆)-alkyl, (C₁₋₆)-alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro and amino, R⁹ and R¹⁰ are identical or different and independently of one another each represents hydrogen, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy, trifluoromethyl, trifluoromethoxy or halogen, R¹¹ and R¹² are identical or different and independently of one another each represents hydrogen or (C₁-C₆)-alkyl, or together with the carbon atom to which they are attached form a (C₄-C₇)-cycloalkyl ring, and R¹³ represents hydrogen, and their pharmaceutically acceptable salts, hydrates and solvates.
 3. Compounds of the general formula (I) according to claim 1 or 2, in which A represents a —CH₂— or —CH₂CH₂— group, X represents O, S or CH₂, R¹, R² and R³ are identical or different and independently of one another each represents hydrogen, (C₁-C₄)-alkyl, (C₁-C₄-alkoxy, chlorine, fluorine, trifluoromethyl, trifluoromethoxy, nitro or cyano, R⁴ represents hydrogen or methyl, R⁵ and R⁶ together with the carbon atom to which they are attached form a carbonyl group, R⁷ represents hydrogen, (C₁-C₄)-alkyl or benzyl, R⁸ represents oxazolylmethyl which may be mono- to trisubstituted by identical or different substituents selected from the group consisting of chlorine, fluorine, bromine, hydroxyl, (C₁₋₄)-alkyl, (C₁₋₄)-alkoxy, trifluoromethyl and amino, R⁹ and R¹⁰ are identical or different and independently of one another each represents hydrogen, (C₁-C₃)-alkyl, (C₁-C₃)-alkoxy, trifluoromethyl, fluorine or chlorine, R¹¹ and R¹² are identical or different and independently of one another each represents hydrogen methyl or ethyl, or together with the carbon atom to which they are attached form a cyclopentyl or cyclohexyl ring, and R¹³ represents hydrogen, and their pharmaceutically acceptable salts, hydrates and solvates.
 4. Compounds of formula (IA)

in which A represents a —CH₂— or —CH₂CH₂— group, X represents O or S, R¹ represents hydrogen, methyl or methoxy, R² and R³ are identical or different and independently of one another each represents methyl, isopropyl, tert-butyl, cyclohexyl, trifluoromethyl, methoxy, trifluoro-methoxy, chlorine or fluorine, and R⁸ represents oxazolylmethyl which may be mono- or disubstituted by methyl.
 5. Medicaments, comprising at least one compound of the formula (I) as defined in claim 1 and inert nontoxic, pharmaceutically suitable carriers, auxiliaries, solvents, vehicles, emulsifiers and/or dispersants.
 6. A method of treating arteriosclerosis comprising administering to a mammal an effective amount of a compound of the formula (I) as defined in claim
 1. 7. Process for preparing medicaments, characterized in that at least one compound of the formula (I) as defined in claim 1 is converted into an administration form using auxiliaries and/or carriers.
 8. Process for preparing compounds of the formula (I) as defined in claim 1, characterized in that [A] compounds of the general formula (II)

in which A, X, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each as defined above and T represents benzyl, (C₁-C₆)-alkyl or a polymeric support suitable for solid-phase synthesis, are initially, with activation of the carboxylic acid group in (II), reacted with compounds of the general formula (III)

in which R¹, R² and R³ are each as defined above, to give compounds of the general formula (Ia)

in which A, X, T, R¹, R², R³, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each as defined above, or [B] compounds of the general formula (IV)

in which A, X, T, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each as defined above are, in the presence of a base, reacted with compounds of the general formula (V)

in which R¹, R², R³ and R⁷ are each as defined above and Q is a suitable leaving group, likewise to compounds of the general formula (Ia) the compounds of the general formula (Ia) are, if appropriate according to known methods for amide alkylation or amide reduction, converted into compounds of the general formula (Ib)

in which A, X, T, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each as defined above then converted with acids or bases into the corresponding carboxylic acids of the general formula (Ic)

in which A, X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each as defined above, and these are, if appropriate according to known methods for esterification, modified further by reaction with compounds of the general formula (VI) R¹³—Z  (VI), in which R¹³ is as defined above and Z represents a suitable leaving group or represents a hydroxyl group. 